Apparent Amnesia

Before euthanasia and thereafter Depression in terminally ill cancer patients and grief in their relatives

Marije L. van der Lee

Cover design:

Xenia Bakker

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Ponsen & Looijen BV, Wageningen

ISBN: Copyright :

© Marije van der Lee 2005

All rights reserved. No part of this publication may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without the prior permission in writing by the author.

Before euthanasia and thereafter Depression in terminally ill cancer patients and grief in their relatives

Voor en na het sterven Depressie en rouw bij terminaal zieke patiënten met kanker en hun familie (met een samenvatting in het Nederlands)

Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. Dr. W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op donderdag 12 mei des ochtends te 10.30 uur door

Marije Liesbeth van der Lee geboren op 22 maart 1973, te Amsterdam

promotoren: Prof. Dr. J. van den Bout Faculteit Sociale Wetenschappen, Universiteit Utrecht Prof. Dr. A.P. M. Heintz Faculteit Geneeskunde, Universiteit Utrecht copromotor: Dr. J. van der Bom Faculteit Klinische Epidemiologie, Universiteit Leiden

The research reported in this thesis was financially supported by the National Foundation of Grief counseling (Landelijke Stichting Rouwbegeleiding) and conducted under the auspices of the Research Institute for Psychology & Health, an Institute accredited by the Royal Dutch Academy of Arts and Sciences.

“Motto”

Contents Chapter 1 Introduction

3

PART I - DEPRESSION AND OTHER SYMPTOMS IN TERMINALLY ILL CANCER PATIENTS AND EUTHANASIA

11

Chapter 2 Screening for depression in terminally ill cancer patients: a single question item

13

Chapter 3 Positive feelings among terminally ill cancer patients

25

Chapter 4 Euthanasia and depression. A prospective cohort study among terminally ill cancer patients

37

Chapter 5 Who wants euthanasia?

53

PART II - EUTHANASIA AND OTHER FACTORS RELATED TO COMPLICATED GRIEF IN THE RELATIVES

69

Chapter 6 Euthanasia: effects on the bereaved. A cross-sectional study

71

Chapter 7 Predictors of complicated grief in relatives of terminally ill cancer patients

85

Chapter 8 Summary and general discussion

101

Dutch summary (Samenvatting in het Nederlands)

117

Acknowledgements (Dankwoord)

119

Curriculum Vitae

120

Publications

121

Chapter 1

Introduction

Chapter 1

During the past century, a shift has arisen in causes of death: acute death has, to a great extent, been replaced by diseases that generally entail a more protracted dying process, such as cancer (1), which is the second leading cause of death in the industrialized world. As a consequence a new discipline in healthcare has been developed: palliative care. This entails the person-centered attention to symptoms, psychological, social and existential distress in patients with limited prognosis, in order to optimize the quality of life of patients and their families or close friends (2). Despite the importance, palliative care has not attracted a lot of research funding (3), even though there are several important issues at the end of life of cancer patients and their family that deserve to be studied empirically (4, 5). This thesis focuses on issues related to psychological well-being in patients and family. More specifically: the recognition of depression in terminally ill cancer patients, the relation between depression and other factors in these patients leading to a request for euthanasia, and the relation between euthanasia and other factors with grief in the relatives. Of course studying a vulnerable patient group has several methodological challenges and ethical drawbacks. One argument that has been given to discourage clinical research in palliative care is that the patient population is too ill and too vulnerable. This argument is disputed by a statement from Duncan Vere: “Ignorance has risks, but they are largely unseen and unnoticed. Gaining knowledge has risks which are noticed, but largely unpredictable, and it is very costly, though less so than prolonged ignorance.” (6) Furthermore the Declaration of Helsinki is accepted as an ethical code and also applies to palliative medicine, therefore one might argue that not giving patients the opportunity to take part in clinical research is unethical (6). Euthanasia The advances in medicine responsible for the shift in causes of death, also allow physicians to prevent or postpone death in patients who formerly would have died. This implies that physicians are far more often confronted with difficult decisions regarding patients’ end of life, including decisions to forgo treatment, alleviation of pain and symptoms with opioids in high dosages and physicianassisted death: euthanasia and physician assisted suicide. Euthanasia is defined as the administration of a drug with the explicit intention of hastening death at the patient’s explicit request. Physician assisted suicide is defined as the 4

Introduction

prescription or supply of potentially lethal drugs to be taken by the patient him- or herself at the patients explicit request with the explicit intention to hasten the patient’s death. Though euthanasia is forbidden in most countries, it has been socially accepted and practised in the Netherlands for the last decennia. In 1991 in the Netherlands a procedure for reporting physicianassisted death was introduced, including criteria for careful practice. The most important criteria that must be fulfilled are: the patients suffering must be hopeless and unbearable, the request must be well considered and made voluntarily, and at least one other physician must be consulted about the first two criteria. In April 2001, the Dutch parliament legalized physician-assisted death. Three nationwide studies conducted in the Netherlands among physicians in 1990/1991, 1995/1996 and 2000/2001, gave insight into the practice of euthanasia and physician-assisted suicide (7-9). The last study was simultaneously conducted in six other European countries, which made it possible to compare end of life decisions between these countries (10). It became clear that euthanasia is predominantly a Dutch practice, while physician assisted suicide is more often practised in Switzerland, where assisted suicide and not euthanasia is allowed. In the Netherlands, approximately 30.000 patients each year ask their doctor if they will assist them to die should suffering become unbearable. Two-thirds of these requests never end up as a serious and persistent request (7, 8, 11). Then of about 9000 explicit requests, two thirds are not carried out and in 31% of these cases depression is a reason for the physician not to grant the request (12), leaving about 3000 patients who die by physician assisted death each year. Euthanasia is responsible for about 2.5 % of all deaths and physician assisted suicide for 0,2%. Of all deaths by euthanasia 80% concern patients with cancer, and in 70% of cases euthanasia is carried out by the general practitioner (13, 14). The most important reasons for the request for euthanasia, as reported by the physician, are the following: futile suffering (65%), loss of dignity (44%), extreme weakness/fatigue (43%) and pain (29%). Although this is valuable information it does not tell us what exactly constitutes unbereable suffering for these patients, from thier perspective. Clinical characteristics reported by the patient that may lead to a request for euthanasia have not been studied thus far.

5

Chapter 1

Depression in terminally ill cancer patients Diagnosing depression in terminally ill cancer patient is difficult because of the overlap in symptoms of depression with symptoms related to cancer or its treatment. The criteria for a Major Depressive Episode, proposed by the American Psychiatric Association are: Presence of at least 5 symptoms for at least 2 weeks (1 or 2 must be included): 1. A depressed mood most of the day nearly every day. 2. Loss of interest or pleasure in almost all activities. 3. Significant weight loss or weight gain. 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day. 6. Loss of energy or great fatique nearly every day. 7. Feelings of worthlessness and guilt nearly every day. 8. Dimished ability to concentrate, or indicisiveness. 9. Recurrent thoughts of death or suicide. Symptoms cause significant impairment in social/occupational function. 8.Symtoms are not directly due to medication, medical condition or bereavement.

Symptoms such as insomnia and loss of weight may be related to cancer or its treatment, as well as to depression. And when patients are in the terminal phase of life it may also be normal to think about death. Despite the complexity in diagnosing depression, it is estimated that about a quarter of terminally ill cancer patients suffer from depressive disorders (15, 16). It goes without saying that depression may have a strong negative impact on the quality of life of patients and their family (17). Euthanasia and depression The concern that depression or suboptimal palliative care would urge patients to pose a request for euthanasia has prompted several studies on factors possibly related to requesting euthanasia. Until now these studies have been 6

Met opmaak: opsommingstekens en nummering

Introduction

executed in countries where euthanasia is not legalised. Some of these studies suggested depression is related with the attitude towards euthanasia, or a wish to hasten death among terminally ill oncology patients (18), while others found no evidence for this relation (19-21). It is clear that the wish or desire to hasten death, cannot be put on par with a well-considered and persistent request for euthanasia. The relation between depression and euthanasia requests can of course only be validly studied in an environment where euthanasia is legalised. Euthanasia and grief After the patient dies from cancer, with or without euthanasia, the families will have to cope with the loss. Grief is a normal reaction to the death of a loved one and will normally not require any professional help, although it increases the risk of psychiatric disorders and illness. Complicated grief, a condition associated with enduring mental and physical health morbidity (22), is the most prevalent psychopathological response to a bereavement event, far exceeding the prevalence of Major Depressive Disorder or Post Traumatic Stress Disorder (23). The proposed criteria for complicate grief are (24): Criterion A 1. Person has experienced the death of a significant other. 2. The response involves intrusive, distressing preoccupation with the deceased person (e.g. yearning, longing, or searching). Criterion B 3. In response to the death, the following symptom(s) is/are marked and persistent: Frequent effort to avoid reminders of the deceased (e.g. thoughts, feelings, activities, people, places); Purposelessness or feelings of futility about the future; Subjective sense of numbness, detachment, or absence of emotional responsiveness. 4. Feeling stunned, dazed, or shocked. 5. Difficulty acknowledging the death (e.g. disbelief). 6. Feeling that life is empty or meaningless. 7. Difficulty imagining a fulfilling life without the deceased. 8. Feeling that part of oneself has died. 9. Shattered worldview (e.g. lost sense of security, trust, or control). 10. Assumes symptoms or harmful behaviours of, or related to, the deceased person. 11. Excessive irritability, bitterness, or7 anger related to the death.

Chapter 1

Criterion C The duration of the disturbance (symptoms listed) is at least two months. Criterion D The disturbance causes clinically significant impairment in social, occupational, or other important areas of functioning.

It is not known whether ending a life of a terminally ill cancer patient with euthanasia carries risk for the development of complicated grief in the relatives. In addition, there have been only few studies that assessed possible predictors of complicated grief in relatives of terminally ill cancer patients, before the death of the patient. Aim and outline of the thesis This thesis is divided in two parts, the first concerns topics related to the patient. The main aim was to study the relation of depression and other symptoms in terminally ill cancer patients, with requesting euthanasia. The second parts handles about the relatives of the patients. The aim was to study the consequences of euthanasia in terminally ill cancer patients for the bereaved and other predictors of complicated grief. Depressive symptoms are the most frequently encountered psychological problems in cancer patients, especially at the end of life. Yet, these symptoms often go unnoticed. Treatment will not be started if depression is not recognized. We studied whether screening with a single question could be of help in recognizing depression and if there are indicators of depression in this group. Results are presented in the second chapter. One other aspect that hinders recognition of depression in cancer patients at the end of life, is that some regard depression in terminally ill cancer patients as normal or inevitable. Since a lot of research attention has been focussed on negative mood in cancer patients, it may seem that cancer patients never experience positive mood at the end of life. Therefore it is interesting to study to what extent positive mood is still experienced by terminally ill cancer 8

Introduction

patients with an estimated life expectance of less than 3 months. Results are described in Chapter 3. The relation between depression and euthanasia is subject of Chapter 4. A nested case-control study was conducted among cancer patients with an estimated life expectancy of less than 3 months. The characteristics of patients who discuss euthanasia with their physician, compared to those who do not, and factors related with an explicit request for euthanasia among those patients who already discussed it, are described in Chapter 5. The second part of this thesis consists of two chapters. In Chapter 6 the bereaved relatives of terminally ill cancer patients who died by euthanasia were compared with the bereaved relatives of terminally ill cancer patients who died as a result of a natural death. Chapter 7 presents predictors of complicated grief 4 and 9 months post-loss, assessed in relatives of terminally ill cancer patients pre-bereavement. The main results of the thesis are summarized, integrated, and discussed in Chapter 8. Methodological considerations, clinical implications and directions for future research will be discussed. References 1.

2.

3. 4.

5.

6.

7.

Van der Maas PJ, Van Delden JJ, Pijnenborg L, Looman CW. Euthanasia and other medical decisions concerning the end of life. Lancet. 1991;338(8768):66974 8. van der Maas PJ, van der Wal G, Haverkate I, et al. Euthanasia, physicianassisted suicide, and other medical practices involving the end of life in the Netherlands, 1990-1995. N Engl J Med. 1996;335(22):1699-705. 9. van der Wal G, van der Heide A, Onwuteaka Philipsen BD, van der Maas PJ. Medische besluitvorming aan het einde van het leven Utrecht: De Tijdstroom; 2003. 10. van der Heide A, Deliens L, Faisst K, et al. End-of-life decision-making in six

Rosen G. A history of public health Baltimore: John Hopkins University Press; 1993. Ahmedzai SH, Costa A, Blengini C, et al. A new international framework for palliative care. Eur J Cancer. 2004;40(15):2192-200. WHO. (World Health Organization). Palliative care: The solid facts. 2004. McQuay H, Moore A. Need for rigorous assessment of palliative care. Bmj. 1994;309(6965):1315-6. Twycross RG. Research and palliative care: the pursuit of reliable knowledge. Palliat Med. 1993;7(3):175-7. Kaasa S, De Conno F. Palliative care research. Eur J Cancer. 2001;37 Suppl 8:S153-9. 9

Chapter 1

11.

12.

13.

14. 15.

16.

17.

European countries: descriptive study. Lancet. 2003;362(9381):345-50. Onwuteaka-Philipsen BD, van der Heide A, Koper D, et al. Euthanasia and other end-of-life decisions in the Netherlands in 1990, 1995, and 2001. Lancet. 2003;362(9381):395-9. Haverkate I, Onwuteaka-Philipsen BD, van der Heide A, Kostense PJ, van der Wal G, van der Maas PJ. Refused and granted requests for euthanasia and assisted suicide in the Netherlands: interview study with structured questionnaire. BMJ. 2000;321(7265):865-6. Groenewoud JH, van der Heide A, Onwuteaka-Philipsen BD, Willems DL, van der Maas PJ, van der Wal G. Clinical problems with the performance of euthanasia and physician-assisted suicide in The Netherlands. N Engl J Med. 2000;342(8):551-6. van der Wal G, Dillmann RJ. Euthanasia in The Netherlands. BMJ. 1994;308(6940):1346-1349. Stiefel R, Die TM, Berney A, Olarte JM, Razavi A. Depression in palliative care: a pragmatic report from the Expert Working Group of the European Association for Palliative Care. Support.Care Cancer. 2001;9(7):477-488. Hotopf M, Chidgey J, Addington-Hall J, Ly KL. Depression in advanced disease: a systematic review Part 1. Prevalence and case finding. Palliat.Med. 2002;16(2):81-97. Valdimarsdottir U, Helgason AR, Furst CJ, Adolfsson J, Steineck G. The unrecognised cost of cancer patients' unrelieved symptoms:a nationwide follow-up of their surviving partners. Br.J Cancer. 2002;20;86(10):1540-1545.

18. Emanuel EJ, Fairclough DL, Daniels ER, Clarridge BR. Euthanasia and physicianassisted suicide: attitudes and experiences of oncology patients, oncologists, and the public. Lancet. 1996;347(9018):1805-10. 19. Suarez-Almazor ME, Newman C, Hanson J, Bruera E. Attitudes of terminally ill cancer patients about euthanasia and assisted suicide: predominance of psychosocial determinants and beliefs over symptom distress and subsequent survival. J Clin Oncol. 2002;20(8):2134-41. 20. Wilson KG, Scott JF, Graham ID, et al. Attitudes of terminally ill patients toward euthanasia and physician-assisted suicide. Arch Intern Med. 2000;160(16):2454-60. 21. Pacheco J, Hershberger PJ, Markert RJ, Kumar G. A longitudinal study of attitudes toward physician-assisted suicide and euthanasia among patients with noncurable malignancy. Am J Hosp Palliat Care. 2003;20(2):99-104. 22. Lichtenthal WG, Cruess DG, Prigerson HG. A case for establishing complicated grief as a distinct mental disorder in DSMV. Clin Psychol Rev. 2004;24(6):637-62. 23. Silverman GK, Johnson JG, Prigerson HG. Preliminary explorations of the effects of prior trauma and loss on risk for psychiatric disorders in recently widowed people. Isr J Psychiatry Relat Sci. 2001;38(34):202-15. 24. Jacobs S, Mazure C, Prigerson H. Diagnostic criteria for traumatic grief. Death Studies. 2000;24(3):185-199.

10

PART I

DEPRESSION AND OTHER SYMPTOMS IN TERMINALLY ILL CANCER PATIENTS AND EUTHANASIA

Chapter 2

Screening for depression in terminally ill cancer patients: a single question item

Marije L. van der Lee Johanna G. van der Bom Jan van den Bout Nikkie B. Swarte Alexander de Graeff A. Peter M. Heintz

Chapter 2

Abstract We set out to study the discriminative ability of a single question about depressed mood and to find somatic, disease, or treatment related variables that may indicate depression in terminally ill cancer patients. A cross-sectional cohort study was conducted among 137 consecutive cancer patients from the University Medical Center Utrecht in the Netherlands. Patients had an estimated life expectancy of three months or less. The single question “Are you depressed?” and the somatic symptoms: pain, drowsiness, appetite, and fatigue, with answers on a ten-point scale, were part of the Edmonton Symptom Assessment Scale. Depression was assessed by the Hospital Anxiety and Depression Scale. The single depression question was able to discriminate the depressed from the non-depressed, the negative predictive value was 96%. Somatic symptoms, most particularly drowsiness, were associated with depression in this terminally ill population. None of the disease or treatment variables showed a clear relation to depression. Introduction About a quarter of terminally ill cancer patients suffer from depressive disorders 1 2, which may have a strong negative impact on the quality of life of patients and their family 3. Patients who are depressed may have physical symptoms that are difficult to palliate and that may ameliorate as their depression is treated 4. Even if life expectancy is short, depression is potentially treatable 5-7. However, treatment will not be started if depression is not recognized. Nurses, general hospital physicians and oncologists have difficulties to recognizing depression in hospitalized patients 8-12. Consequently a large proportion of the psychiatric morbidity which develops in cancer patients may go unrecognized and therefore untreated 13. Several factors may influence the recognition of depression in terminally ill patients. Firstly, little is known about indicators of depression in this group. General indicators of depression such as female gender, may not be related to depression in terminally ill patients. Another problem with the recognition of depression in cancer patients is the overlap between symptoms of disease and symptoms of depression. Symptoms such as insomnia and loss of appetite may be related to cancer or its treatment, as well as to depression. From the scarce 14

Screening for depression in terminally ill

literature about the relation between somatic symptoms and depression in cancer patients we expect that some symptoms, in particular appetite and ability to think may help to discriminate depressed from non depressed terminally ill patients 14. Another factor that can hinder the recognition of depression is that many accept a depressed mood as a normal consequence of terminal illness and are therefore reluctant to treat it. This idea may exist in patients as well as in physicians and nurses. But what seems ‘normal’ under abnormal circumstances can still cause unnecessary suffering, and suffering from depression can be considered unnecessary since it is potentially treatable. Maybe an analogy with pain can make this clear: pain is also common in patients with terminal illness, but this will not be a reason not to treat it as it can be treated and treatment will reduce suffering. There is good evidence that screening improves the accurate identification of depressed patients in primary care settings, and the benefits of screening are likely to outweigh any potential harms when positive screening results are followed by accurate diagnosis, effective treatment and careful follow-up 15 16. It is not clear whether this also holds for terminally ill patients. If so, the optimum strategy would be to systematically screen all terminally ill patients for depression with a validated questionnaire and subsequently refer selected patients for a clinical interview. In practice this is considered too burdensome for this frail group of patients. Recent findings about simply asking "Are you depressed?" in a palliative population as an alternative to the currently used questionnaires yielded inconclusive results 17 18. If the discriminative ability of a simple question is comparable to that of a validated questionnaire, considerable time and energy may be won to the advantage of severely ill patients. We therefore set out to study the discriminative ability for depression of a single question about depressed mood and to find somatic, disease or treatment related variables that may indicate depression in terminally ill cancer patients. Methods Patients As part of a study into the relation between depression and euthanasia, we interviewed cancer patients with an estimated life expectancy of three months or less, in the period between September 1999 and August 2003. The cohort 15

Chapter 2

comprised consecutive cancer patients from the departments of gynecology, medical oncology, lung diseases, and head and neck surgery of the University Medical Center Utrecht in The Netherlands. The University Medical Center Utrecht is one of the ten tertiary referral centers for cancer patients in the Netherlands. A patient was eligible for inclusion into the cohort if he or she had cancer and the attending physician estimated his/her life expectancy to be three months or less, and thought the patient able to participate. That is, the patient was aware the cancer was untreatable and the patient was able to answer questions regarding anxiety and depression. When the physician determined a patient eligible for inclusion into the cohort he or she approached the patient. The reasons the physicians gave for excluding a patient, were carefully noted. The reasons the patients gave for refusing to participate were also recorded. When a patient decided to participate in this study, he or she was requested to sign an informed consent form. Thereafter the patient could fill out the questionnaires by him/herself or with help from the researcher. Most inpatients chose the latter option and the questionnaire was then presented orally by the interviewer. The study was approved by the Medical Ethics Committee at the University Medical Center Utrecht. Measures Of each patient the following items were recorded from the medical files (including nurses reports and electronic file information): demographic items (such as gender, religion, marital status and age at moment of inclusion), medical history (previous surgery, radiotherapy or chemotherapy, whether pain was adequately controlled in the week before the questionnaire was administered and thereafter, consultations of psychologist or psychiatrist, and whether the patient received medication for depression, and/or pain). The physician or nurse rated the patient’s functional level on the Karnofsky Performance Status Scale. The Karnofsky Performance Status Scale is widely used to quantify the functional status of cancer patients and is generally considered to be a valuable research tool 19. Scores can range from 100 (no symptoms and no functional limitation in activities of daily living) to 0 (indicating that the patient has died). . Depression was assessed by the Hospital Anxiety and Depression Scale (HADS) 20. The HADS is a 14-item self-report scale that focuses on depressed 16


mood to bypass the problem of the overlap of physical symptoms. Each item is rated on a scale from 0 (“not at all”) to 3 (“very much”). When using the HADS for screening for depression in a palliative setting a cut-off score of 20 for the total scale (instead of using two separate scales) is recommended 21. The single question “Are you depressed?” was part of the Edmonton Symptom Assessment Scale (ESAS), an instrument validated in palliative care settings 22. The answer could be given on a ten point scale from 0 (“not at all depressed”) to 10 (“severely depressed”). It has been suggested that among critically ill patients several symptoms are present that are not covered by the items in the original ESAS and to use a numerical instead of visual scale 23. For this reason fatigue, sadness, confusion and dependence, were added to the ESAS. Each symptom was rated from 0 (“not at all”) to 10 (“very much”). Statistical analysis It has been shown that deleting subjects with a missing value on one of the independent variables (so called complete case analyses) commonly leads to biased results and to a loss of power 24. Imputation may serve to overcome the bias due to missing data in diagnostic research and to increase the efficiency of the analysis, therefore missing values in the questionnaires were imputed using the expectation maximization method 25. Such imputation is based on the correlation between each variable with missing values and all other variables as estimated from the complete subjects. A ROC curve was plotted for the depressed mood, anxiety, and sadness question. The area under receiver operating characteristic curve (ROC area) was used to quantify the discriminative ability of these questions. For clinical use the positive and negative predictive values are also given. In addition, all potential indicators of depression were analyzed in univariate analyses. Computations and imputations were performed by using SPSSVersion 11.5 for Windows package (SPSS Inc, Chicago, IL). Results Between September 1999 and July 2003 385 cancer patients were traced who had a life expectancy of less than 3 months, 187 patients were deemed unable to participate in the study by their physician. We asked 198 patients to participate. Of these, 40 refused (4 because of fatigue, 6 were too ill, 8 too distressed, 2 did 17

Chapter 2

Table 1 Demographic, tumour, disease and treatment characteristics according to presence or absence of depression. Depressed Not depressed (n=32) (n=105) Female 18 (56) 70 (67) Age, years 58 (35-81) 60 (22-84) Married or cohabiting 22 (69) 72 (67) Children (yes) 24 (75) 77 (73) Religious (yes) 10 (31) 47 (45) Inpatient (yes) 27 (84) 89 (85) Tumour localization Mammae 5 (16) 8 (8) Gastro Enterology 4 (13) 13 (12) Lung 2 (6) 6 (6) Urological 6 (19) 17 (16) Gynaecological 7 (22) 42 (40) Head – Neck 5 (16) 12 (11) Others 3 (9) 7 (7) Functional status (Karnofsky) 51 (30-80) 56 (20-100) Median actual survival after inclusion, days 34 (2-328) 56 (1-683) Median time since incurable at inclusion, months 2.48 (0-28) 2.85 (0-69) History of curative and palliative operations, number 1 (0-3) 1 (0-3) History of curative radiotherapy, number 1 (0-3) 0 (0-3) History of palliative radiotherapy, number 1 (0-3) 0 (0-3) History of curative chemotherapy, number 1 (0-3) 0 (0-3) History of palliative chemotherapy, number 0 (0-2) 0 (0-3) Pain medication (yes) 31 (97) 99 (93) Uncontrolled pain documented in medical status in week before inclusion (yes) 12 (38) 16 (15) Diagnosis depression documented in Medical status (yes) 2 (6) 4 (4) Antidepressant medication (yes) 10 (31) 9 (9) Values are numbers (%) or means (range), unless stated otherwise.

not accept being incurable, 2 were not aware of being incurable, 18 for other reasons such as not being interested) and 18 gave consent but were not able to complete the questionnaire. No differences in age or gender were found 18


between the patients that participated and those who were not able or refused to participate. Three participants had more than 10% missing data and were therefore excluded from the analysis, leaving 137 patients. Of nine participants only one ESAS question was missing, seven participants missed between two and five questions and, six persons missed more than five questions of the ESAS. Of 15 persons the Karnofsky Performance Status Scale score was missing. All missing data from the ESAS and Karnofsky Performance Status Scale were imputed. Table 1 presents the characteristics of the cohort according to presence or absence of depression. At the time of analysis 126 patients had died. Their median survival after completing the questionnaire was 43 days (range 1-683). Median time between when the patients were told about having cancer and administration of the questionnaire was 20 months; median time since being told that the cancer was incurable and administration of the questionnaire was 3 months. Thirty-two patients (23%) were depressed as assessed by the HADS questionnaire (score > 20 points). The single question about depressed mood (ESAS) most strongly discriminated patients with depression from those without depression. The area under the ROC curve was highest for the single-depression question: 87% (95%CI: 80-93), compared to a single question about anxiety: 85% (95%CI: 7693) and sadness: 81% (95%CI: 72-90). A score of > 2 on the single depression question had a positive prediction value of 30/74 (40%); a score of < 2 had a negative predictive value of 61/63 (96%) (Table 2). Thus, a score of < 2 virtually excluded a depression as assessed by the HADS. Table 2 Number of patients depressed according to the single question and the HADS*. Are your depressed? Depressed (> 2) Not depressed (< 2) Depressed 30 2 Not Depressed 44 61 Total 74 63 * Hospital and Anxiety Scale.

As can be read from Table 3, Model 1, pain, drowsiness, appetite and fatigue were statistically significantly related to depression, most particularly drowsiness. Psychological symptoms were all related to depression (Table 3, 19

Chapter 2

Model 2). None of the disease or treatment variables showed a clear relation to depression (Table 3, Model 3). Analyses were repeated after excluding eleven patients on antidepressant medication at inclusion; overall the results did not materially change. Table 3 Univariate association between potential indicators and presence of depression.* Odds Ratio (95% CI) Somatic symptoms Pain (per point, range 1-10)† 1.25 (1.08-1.44) Drowsiness (per point, range 1-10) 1.51 (1.26-1.81) Appetite (per point, range 1-10) 1.24 (1.09-1.41) Fatigue (per point, range 1-10) 1.39 (1.16-1.67) Psychological symptoms Depression (per point, range 1-10) 1.75 (1.43-2.15) Sadness (per point, range 1-10) 1.62 (1.35-1.94) Anxiety (per point, range 1-10) 1.49 (1.28-1.74) Confusion (per point, range 1-10) 1.29 (1.11-1.51) Well-being (per point, range 1-10) 1.65 (1.35-2.02) Dependence (per point, range 1-10) 1.37 (1.14-1.64) Demographic, disease or treatment related Male 1.51 (0.68-3.39) Married or cohabiting 1.01 (0.43-2.37) Children (yes) 1.17 (0.84-1.64) Religion (yes) 0.48 (0.20-1.16) Age, years 0.99 (0.95-1.02) Actual survival after inclusion, days 0.99 (0.99-1.00) Time since incurable at inclusion, months 0.98 (0.93-1.02) Functional status (Karnofsky) (per point, range 0-100) 0.98 (0.96-1.01) History of curative radiotherapies, number 0.91 (0.53-1.52) History of palliative radiotherapies, number 1.11 (0.71-1.76) History of curative chemo therapies, number 1.62 (0.93-2.83) History of palliative chemo therapies, number 0.73 (0.39-1.37) History of curative and pallative operations, number 0.75 (0.54-1.04) Pain in medical status wk before (yes) 1.44 (0.88-2.28) Pain medication 2.08 (0.24-18.01) * According to the Hospital Anxiety and Depression Scale. † With each point the patient scores higher, the given odds ratio increases. Obtained by logistic regression analysis with depression as dependent variable. 20


Discussion In this study we found that the discriminative ability of a single question about depressed mood on a scale from zero to ten was good. Quite remarkably, somatic symptoms were found to indicate depression in this terminally ill population, even though depression was measured by an instrument that does not include physical symptoms. Demographic, disease or treatment variables that may have a relation with depression in a non-terminally ill population, did not contribute to the discrimination between depressed and non-depressed terminally ill patients. To appreciate these findings some aspects regarding the design of the study need to be discussed. Firstly, results were based on the questionnaires from 137 patients, leaving out 177 palliative oncology patients that could not be asked and 48 patients that did not want or were not able to participate, most often due to reasons inherent to being terminally ill. As a result the prevalence of psychological and physical symptoms may be underestimated. It is not clear whether a higher prevalence would yield higher or lower discriminative abilities. At least, the prevalence of depression in our sample was comparable to other studies 26 27. Secondly, we assessed depression by the Hospital Anxiety and Depression Scale (HADS), an often used, valid and reliable screening instrument for depression in a palliative care setting 21 28. The HADS is, however, not a golden standard for the assessment of depression and therefore our results pertaining to the single question must not be understood as an easy method to the diagnosis of depression, but as a more efficient approach to screening for depression. Thereby we take the stance that identifying patients falsely as depressed will be less harmful than missing patients that could have been offered treatment. A previous study that tested the validity of a single item interview on depression among 197 terminally ill patients found a 100% positive predictive value 17. However it has been argued that the results of this study were biased because it included the single question in the schedule of the interview with which it was compared 18. Our results were not biased in that sense, since we compared the single question with a questionnaire that focuses on depressed mood. The discriminative ability of a single question found in this study was better then that found in another study, which also did not include the single 21

Chapter 2

question in the schedule of the interview with which it was compared 18. The difference with our study is that other investigators used a dichotomous answer category, where we used a ten-point scale, which may give more room to nuance and therefore discriminate better. Our finding concerning the relation between somatic symptoms and depression were consistent with findings from a study that explored how to use somatic symptoms appropriately in diagnosing depression (according to DSM IV criteria) in cancer patients 14. It partly solves the well-known difficulty with somatic symptoms in terminally ill patients namely that it is unclear whether these symptoms are depression-, disease- or treatment-related. Regardless of the cause of these symptoms, it seems that self-reported somatic symptoms such as drowsiness should alert clinicians for the potential presence of depression. Besides it is highly probable that there is a mutual relation between depression and somatic symptoms 29. Depression may aggravate the presence or perception of somatic symptoms and the presence of somatic symptoms on its turn may heighten the risk for depression. Treatment of depression can stop this process of reciprocal negative influence 4. When patients are judged by their physician to be in the last months of life, factors that are normally related to depression such as female gender or performance status, are apparently overridden. Other indicators of depression, such as drowsiness, can therefore be helpful, as well as asking the patient to score his depressed mood on a 10-point scale. If a patient scores higher than 2, we recommend to pose some additional questions about the duration of the depressed mood. If the mood has been present continuously for at least 2 weeks, treatment should be offered 5-7. This is all important information since depression often goes unrecognized and therefore untreated in this group of patients. We conclude that when it comes to screening for depression in terminally ill the most efficient approach seems to start by asking for depression with one simple question. Acknowledgements The authors thank Froukje Vernooy and Susanne Dalmeier for their help in collecting data and interviewing patients. They also thank all physicians who took part in the study. 22


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Stiefel R, Die TM, Berney A, Olarte JM, Razavi A. Depression in palliative care: a pragmatic report from the Expert Working Group of the European Association for Palliative Care. Support.Care Cancer 2001;9(7):477-488. Hotopf M, Chidgey J, Addington-Hall J, Ly KL. Depression in advanced disease: a systematic review Part 1. Prevalence and case finding. Palliat.Med. 2002;16(2):81-97. Valdimarsdottir U, Helgason AR, Furst CJ, Adolfsson J, Steineck G. The unrecognised cost of cancer patients' unrelieved symptoms:a nationwide follow-up of their surviving partners. Br.J Cancer 2002;20;86(10):1540-1545. Lloyd Williams M, Payne S. A qualitative study of clinical nurse specialists' views on depression in palliative care patients. Palliat Med 2003;17(4):334-8. Homsi J, Nelson KA, Sarhill N, Rybicki L, LeGrand SB, Davis MP, et al. A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 2001;18(6):403-7. Block SD. Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians American Society of Internal Medicine. Ann Intern Med 2000;132(3):209-18. Greer S, Moorey S, Baruch JD, Watson M, Robertson BM, Mason A, et al. Adjuvant psychological therapy for patients with cancer: a prospective randomised trial. Bmj 1992;304(6828):675-80. Stromgren AS, Groenvold M, Sorensen A, Andersen L. Symptom recognition in advanced cancer. A comparison of nursing records against patient self-rating. Acta Anaesthesiol.Scand. 2001;45(9):1080-1085.

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Stromgren AS, Groenvold M, Pedersen L, Olsen AK, Spile M, Sjogren P. Does the medical record cover the symptoms experienced by cancer patients receiving palliative care? A comparison of the record and patient self-rating. J.Pain Symptom.Manage. 2001;21(3):189-196. Balestrieri M, Bisoffi G, Tansella M, Martucci M, Goldberg DP. Identification of depression by medical and surgical general hospital physicians. Gen.Hosp.Psychiatry 2002;24(1):4-11. Sollner W, DeVries A, Steixner E, Lukas P, Sprinzl G, Rumpold G, et al. How successful are oncologists in identifying patient distress, perceived social support, and need for psychosocial counselling? Br.J Cancer 2001;84(2):179-185. Horton R. Differences in assessment of symptoms and quality of life between patients with advanced cancer and their specialist palliative care nurses in a home care setting. Palliat Med 2002;16(6):488-94. Lloyd-Williams M. Difficulties in diagnosing and treating depression in the terminally ill cancer patient. Postgrad Med J 2000;76(899):555-8. Akechi T, Nakano T, Akizuki N, Okamura M, Sakuma K, Nakanishi T, et al. Somatic Symptoms for Diagnosing Major Depression in Cancer Patients. Psychosomatics 2003;44(3):244-248. Pignone MP, Gaynes BN, Rushton JL, Burchell CM, Orleans CT, Mulrow CD, et al. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136(10):765-76. Arroll B, Khin N, Kerse N. Screening for depression in primary care with two

Chapter 2

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verbally asked questions: cross sectional study. Bmj 2003;327(7424):1144-6. Chochinov HM, Wilson KG, Enns M, Lander S. "Are you depressed?" Screening for depression in the terminally ill. Am.J.Psychiatry 1997;154(5):674-676. Lloyd-Williams M, Dennis M, Taylor F, Baker I. Is asking patients in palliative care, "are you depressed?" Appropriate? Prospective study. Bmj 2003;327(7411):3723. Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale. An examination of its reliability and validity in a research setting. Cancer 1984;53(9):2002-2007. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67(6):361-70. Le Fevre P, Devereux J, Smith S, Lawrie SM, Cornbleet M. Screening for psychiatric illness in the palliative care inpatient setting: a comparison between the Hospital Anxiety and Depression Scale and the General Health Questionnaire-12. Palliat.Med. 1999;13(5):399-407. Philip J, Smith WB, Craft P, Lickiss N. Concurrent validity of the modified Edmonton Symptom Assessment System with the Rotterdam Symptom Checklist and the Brief Pain Inventory. Support Care Cancer 1998;6(6):539-41. Rees E, Hardy J, Ling J, Broadley K, A'Hern R. The use of the Edmonton

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Symptom Assessment Scale (ESAS) within a palliative care unit in the UK. Palliat Med 1998;12(2):75-82. Oostenbrink R, Moons KG, Bleeker SE, Moll HA, Grobbee DE. Diagnostic research on routine care data: prospects and problems. J Clin Epidemiol 2003;56(6):5016. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995;142(12):1255-64. Lloyd-Williams M, Friedman T. Depression in palliative care patients--a prospective study. Eur J Cancer Care (Engl) 2001;10(4):270-4. Power D, Kelly S, Gilsenan J, Kearney M, O'Mahony D, Walsh JB, et al. Suitable screening tests for cognitive impairment and depression in the terminally ill--a prospective prevalence study. Palliat Med 1993;7(3):213-8. Lloyd-Williams M, Friedman T, Rudd N. An analysis of the validity of the Hospital Anxiety and Depression scale as a screening tool in patients with advanced metastatic cancer. J.Pain Symptom.Manage. 2001;22(6):990-996. Portenoy, RK. Physical Symptom Management in the Terminally ill. In: Chochinov HM, Breitbart W, eds. Handbook of psychiatry in palliative medicine. London: Oxford University Press, 2000: 99 – 130.

Chapter 3

Positive feelings among terminally ill cancer patients

Marije L. van der Lee Nikkie B. Swarte Johanna G. van der Bom Jan van den Bout A. Peter M. Heintz

Chapter 3

Abstract Aim: For a realistic perspective on what it is like to have cancer and be in the last months of life, it is necessary to also study the positive feelings people may still experience. We set out to describe positive feelings experienced by terminally ill patients. Methods: The Depression Adjective Checklist was completed by 96 cancer patients with an estimated life expectancy of less than three months. Results: On average patients endorsed 30% (3.6/12) of the positive mood items, and 25% (5.4/22) of the negative mood items. The larger part of terminally ill cancer patients with an estimated life expectancy of less than three months reported one or more positive mood states. A positive mood state such as ‘being interested’ (65%) was more common than ‘feeling sad’ (56%). Conclusion: Though having incurable cancer often leads to feelings of depression, positive feelings seem to be common. Introduction One in four lives will end with cancer in the developed world 1. The diagnosis of untreatable cancer will evoke an image of misery in most of us. Indeed pain and other physical symptoms are common among terminally ill cancer patients and up to a quarter suffer from depressive disorders 2. A lot of studies have focused on the prevalence of depression and other disorders in palliative care, and this knowledge is relevant for the prevention of unnecessary distress 3-10. Yet, a consequence of the fact that research on negative mood states in palliative care has dominated the literature may be that positive mood states are regarded as rare or even abnormal. It is less recognized that patients with cancer are often able to cognitively restructure their life situations and create meanings 11 which likely results in more positive mood. Apart from the literature about the importance of maintaining hope and spirituality 12 in the light of terminal illness, we are not aware of any report about positive mood states in persons with advanced cancer. It has been demonstrated that experience in care for terminally ill patients or education in palliative care, results in a more positive attitude towards care for these patients 13. Knowledge about positive feelings in people suffering from 26

Positive feelings in terminally ill

advanced disease may contribute to a more positive attitude in persons caring for these patients and in the (future) patients themselves. We set out to study the prevalence of positive mood states in terminally ill cancer patients. Furthermore we explore relations between positive mood and gender, age, marital status, depression, survival and functional status. Patients and methods Patients As part of a study into the relation between depression and euthanasia, we interviewed cancer patients with an estimated life expectancy of three months or less, in the period between June 2000 and August 2003. The cohort comprised all consecutive cancer patients from the departments of gynaecology, medical oncology, lung diseases, and head and neck surgery of the University Medical Center Utrecht in The Netherlands. This hospital is one of the ten tertiary referral centres for cancer patients in the Netherlands. A patient was eligible for inclusion into the cohort if he or she had cancer and the attending physician estimated his/her life expectancy to be three months or less, and thought the patient able to participate. That is, the patient was aware the cancer was untreatable and the patient was able to answer questions regarding mood state. When the physician determined a patient eligible for inclusion into the cohort he or she approached the patient. When a patient decided to participate in this study, he or she was requested to sign an informed consent form. Thereafter the patient could complete the questionnaires by him/herself or with help from the researcher. Most inpatients chose the latter option and the questionnaire was then presented orally by the interviewer. The study was approved by the Medical Ethics Committee at the University Medical Center Utrecht. Measures Of each patient demographic items (such as gender, religion, marital status and age at moment of inclusion) were recorded from the medical files. The treating physician or nurse rated the patient’s functional level on the Karnofsky Performance Status Scale. The Karnofsky Performance Status Scale is widely used to quantify the functional level of cancer patients and is generally 27

Chapter 3

considered to be a valuable research tool 14. Scores can range from 0 (indicating that the patient has died) to 100 (no symptoms and no functional limitation in activities of daily living). The Hospital Anxiety and Depression Scale (HADS) was used to assess “depressed mood”; we used a cut-off score of 20 for the total scale 15. Positive mood states were assessed by the Dutch version of the Depression Adjective Checklist 16. The Depression Adjective Checklist contains 12 positive mood items and 22 dysphoric items and the respondent is asked to mark all words that reflect his or her general mood state of last week. Statistical analysis The prevalence of the specific positive mood states are given. ANOVA’s were done to calculate whether there were statistically significant differences between people with or without depressed mood, with or without a religion, living with or without a partner. Linear regression analyses were performed to assess the influence of age, survival and functional status on total number of positive mood items that were endorsed. Computations were performed by using Statistical Package for Social Services Version 11.5 for Windows package (SPSS Inc, Chicago, IL). Results We asked 123 patients to complete the Depression Adjective Checklist, of whom 96 patients did so; the remainder of patients was too ill or too tired to participate. Most patients (84%) completed it in the hospital, 16 % completed it at home. Table 1 shows that more than half of the cohort was female, married, the mean age was 59 years and the tumour site was mostly gynaecological or urological. Anti tumour treatment was discontinued at a median period of 2,8 months before inclusion. More than a third of patients (33%) were bedridden; another 12% needed frequent medical assistance and care as judged by the physician or nurse on the Karnofsky Performance Scale. The remainder of patients was more or less capable to care for themselves. Religious affiliation was indicated in the medical status of 78 persons; 39 patients said to have no religious affiliation. Median survival after completing the questionnaire was 48 days (range 2 days-years). On average patients endorsed 30% (3.6/12) of the positive mood items, and 25% (5.4/22) of the negative mood items. Although over half of the patients felt 28


sad (56%), a larger proportion of patients (65%) indicated that they felt interested (Table 2). In addition more than a third of patients indicated feeling positive emotions such as: jovial, optimistic, merry, or fine. A quarter of patients also indicated feeling whole, enthusiastic or alive. One in five patients even felt elated or healthy. Nineteen (20%) of all patients seem to have a total absence of positive mood; another eighteen patients indicated only one positive mood. The rest of the patients (51%) indicated the presence of two to twelve positive mood states. Twenty-two % of patients had a depressed mood as assessed by the Hospital Anxiety and Depression Scale. Among these patients there was an absence of positive mood state in 9 (43%) and one positive affect indicated in 10 (47%), compared to an absence of positive mood in 10 (13%) of the non depressed patients. Table 1 Demographic, tumour, and disease characteristics. (n=69) Female 60 (63) Age, years 59 (32-84) Married or cohabiting (yes) 67 (70) Children (yes) 74 (77) Religious (yes)* 41 (43) Inpatient 82 (84) Tumour site Breast 10 (10) Gastro Intestinal 12 (13) Lung 8 (8) Urological 16 (17) Gynaecological 32 (33) Head and Neck 10 (10) Others 8 (8) Functional status (Karnofsky)† 55 (20-100) Median actual survival after inclusion, days‡ 48 (2-937) Median time since incurable at inclusion, months 2.82 (0-43) Note. Values are numbers (%) or means (range), unless stated otherwise. * Missing for 16 persons. † Missing for 8 persons. ‡ Five persons still alive.

29

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Table 2 Prevalence of positive and negative mood states among terminally ill cancer patients, in order of frequency. Number (%) Interested 62 (65) Sad 54 (56) Bleak 42 (44) Drained 41 (43) Miserable 41 (43) Heartstick 36 (38) Jovial 36 (38) Optimistic 33 (35) Gloomy 32 (33) Merry 31 (33) Fine 31 (32) Depressed 31 (32) Glad 29 (30) Whole 27 (28) Alive 26 (27) Enthusiastic 26 (27) Afflicted 24 (25) Dull 24 (25) Melancholy 24 (25) Alone 20 (21) Heavy – harted 20 (21) Desolate 20 (21) Oppressed 20 (21) Lonesome 19 (20) Elated 19 (20) Healthy 18 (19) Despondent 18 (19) Sunk 13 (14) Lifeless 13 (14) Grief stricken 11 (12) Failure 8 (8) Eager 6 (6) Unwanted 3 (3) Gruesome 3 (3)

Women reported more positive affect on average than men did (4.2 versus 2.6; p < .03), while no difference was found between men and women concerning the average number of negative mood states they indicated (5.6 and 5.0 respectively). We compared positive mood states of women with those of men. Five positive mood items were reported statistically significantly more often by women than men: interested (75% versus 48%), elated (28% versus 6%), optimistic (42% versus 23%), merry (40% versus 20%), and whole (33% versus 20%). No difference was found in the mean number of positive mood states between religious people and those who were not religious, people who completed the questionnaire in the hospital or at home and between people living alone or people living with a partner. No relationship was found between positive mood states and age, survival after completing the questionnaire, or number of months the patients knew the cancer was incurable (Table 3). Though there was no significant direct effect of functional status on positive mood, we did find an interaction effect between sex and functional status on positive mood (Table 3). Women experienced more positive mood states when they were more able to care for themselves, whereas there was no such relation for men. Men and women did not differ on average functional status, thus the finding that women reported more positive mood than men could not be explained by a higher functional status. Table 3 Univariate relations with positive moods reported obtained by linear regression. 30


Age, years Actual survival after inclusion, days Time since incurable at inclusion, months Functional status (Kamofsky) (per point, range 0-100) Interaction term functional status and sex ** p < .01.

B -.03 .00 .00 .04 -.10

SE B .03 .00 .03 .03 .038**

Discussion The larger part of terminally ill cancer patients with an estimated life expectancy of less than three months reported one or more positive mood states. Despite their condition, these patients apparently still experienced a large range of positive mood states. A positive mood state such as ‘being interested’ was more common than ‘feeling sad’. More than half of the patients indicated feeling interested and more than a third expressed feeling fine, optimistic or jovial in general. Only a minority of patients (20 %) had an absence of positive affect. Women expressed more positive mood states than men; while at the same time they did not report more negative emotions. As was expected, depressed patients indicated less positive mood. A higher functional status as judged by the physician or nurse, was only related to less positive mood in women, not in men. To appreciate these findings some limitations regarding the design of the study need to be discussed. Firstly, results were based on the questionnaires from 96 patients, leaving out 27 patients that did not want or were not able to participate, most often due to reasons inherent to being terminally ill. As a result the prevalence of positive mood states may be overestimated. The prevalence of depression (which is inversely related to positive mood) in our sample was comparable to other studies though 2 10 17, suggesting that at least our cohort is comparable to previously studied cohorts of terminally ill patients. Secondly, positive mood was self-reported in this study. Possibly patients are inclined to confirm, when asked for 34 mood states in a row. However, this is contradicted by the fact that more people indicated positive emotions than

31

Chapter 3

Figure 1 Mean of positive mood states for not depressed and depressed male and female

negative emotions, while there were more negative emotions in the list (12 positive and 22 negative). Perhaps it is more socially desirable to answer ‘yes’ to positive mood states, but since the study was introduced as research into depression and anxiety among people with incurable cancer we don’t think social desirability has influenced our findings. In addition to this the instruction with the questionnaire was: ‘Have you felt a particular mood last week in general, that is: most of the time?’. We think this instruction does not invite people to confirm more easily to questions regarding positive moods. These findings may conflict with the image some people have of terminal ill patients, but are in line with earlier research in the field of trauma and bereavement. The assumption that positive emotions in the face of loss or trauma are rare and even pathological has been disputed 18 19. We are not aware 32


of studies into the prevalence of positive mood states among terminally ill cancer patients, though one study reported positive feelings in chronically ill, who were close to death 20. The findings also fit in the theory of cognitive adaptation, which implies that through a search for meaning, regaining mastery and enhancing self-esteem, people adjust to threatening events 11. The theory of cognitive adaptation evolved from an interview study with breast cancer patients. These women gave a higher priority to relationships after cancer, and among others held the illusion that they could control their cancer. The illusion of control of the cancer must have been shattered in our group of patients, still the majority seem able to cognitively adapt to the situation considering the range of positive mood reported. Women tend to be somewhat more emotionally expressive than men. In previous studies this sex difference was also found particularly for the expression of positive (and not negative) mood 21 22. Since expression and experience of positive emotions have been found to be positively related 23, this may mean that women are better able to adapt. An explanation can be found in different coping styles: women use ways of coping that take into account interpersonal and emotional aspects of the situation in a more complex and integrated fashion, whereas men generally engage more in problem solving coping which is less helpful in this phase of the disease 24. The reason for the fact that the experience of positive mood was related to functional status in women and not in men may also lie in different coping styles. The extent to which positive mood states buffer against negative ones warrants further exploration. Positive emotions in healthy and bereaved individuals have been shown to reduce levels of distress following general aversive events both by quieting or undoing negative emotion 25 26. This may also hold for people suffering from cancer, even in the last months of life. The finding that the ability to find meaning is associated with a less rapid course of illness 27 was not supported in this study where patients where in the last months of life. Though having incurable cancer often leads to feelings of depression, the majority of people who are aware that they will die from cancer, seem still able to experience positive mood states in the last months of life, despite their condition.

33

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Acknowledgements The authors thank Froukje Vernooy and Susanne Dalmeier for their help in collecting data and interviewing patients. They also thank all physicians who took part in the study. The study was funded by the Research Institute for Psychology and Health, and by the Department of Gynaecology, University Medical Center Utrecht. References 1.

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Chapter 4

Euthanasia and depression A prospective cohort study among terminally ill cancer patients

Marije L. van der Lee Johanna G. van der Bom Nikkie B. Swarte A. Peter M. Heintz Alexander de Graeff Jan van den Bout

Chapter 4

Abstract Background: Some patients with advanced cancer express the wish for euthanasia. Underlying depression has been suggested to be responsible for these wishes. Objective: To study the association between depression and the incidence of explicit requests for euthanasia in terminally ill cancer patients. Design: Prospective cohort study. Setting: The departments of gynecology, medical oncology, lung diseases, and head and neck surgery of the University Medical Center Utrecht, the Netherlands. Patients: 138 consecutive cancer patients with an estimated life expectancy of three months or less. Measurements: Hospital Anxiety and Depression Scale. To diagnose “depressed mood” we used a cut-off score of 20. Endpoints: A consistent request for euthanasia. Results: Of all 138 patients, 32 patients had a depressed mood at inclusion. Thirty patients (22 %) did an explicit request for euthanasia. The risk to request euthanasia for patients with depressed mood was 4.1 (95%CI 2.0 to 8.5) times higher than that of patients without depressed mood at inclusion. Conclusions: Depressed mood in cancer patients with an estimated life expectancy of less than three months is associated with a higher likelihood to request for euthanasia. The question whether depressed mood can adequately be treated in this terminally ill population and if so, whether it would lower the incidence of requests for euthanasia, needs further investigation. Introduction Euthanasia and physician-assisted suicide are hotly debated issues. Opposition partly stems from the perspective of suicide as a symptom of mental illness and the tendency to extend this view of suicide in the medically well to euthanasia and physician-assisted suicide in the terminally ill (1). Recent studies among terminally ill patients found that a desire for hastened death or interest in assisted suicide was associated with depression (2-12). It has therefore been suggested that a request for euthanasia may be a symptom of depression and that the depression should be treated prior to granting the request for 38

Euthanasia and depression

euthanasia (11, 13, 14). There are two reasons why we felt uncomfortable with this idea. First, the constructs previously studied, such as the wish to hasten death, cannot be put on par with a well-considered and persistent request for euthanasia in an environment where euthanasia is customary. The relation between depression and euthanasia requests can only validly be studied in an environment where euthanasia is legalized. Second, in our experience requests for euthanasia are mostly well considered and commonly not associated with depression. Terminally ill cancer patients who request euthanasia often do so from a position of acceptance of their impending death, rather than their request being driven by an underlying psychiatric disturbance. We, therefore, expected that patients requesting euthanasia might be even less depressed. Patients that are aware of their limited life expectancy, and are able to talk about this openly, more often speak about their desire for euthanasia (15). Accordingly, it was suggested that patients who deny their prognosis or are uncertain about their impending death may be more depressed or anxious (16, 17). So far, only The Netherlands and Belgium have legalized euthanasia. Euthanasia is defined as the intentional termination of the life of a patient at their explicit request by a physician. In The Netherlands three nation-wide studies on the medical practice concerning the end of life were conducted. The most recent study shows the rate of euthanasia to be 7.4% of all cancer deaths (18-20). These studies have greatly contributed to the debate about the role of euthanasia in modern health care. However, whether depression is associated with requesting euthanasia has not been studied (18).

The aim of this study was to investigate whether depression in terminally ill oncology patients is associated with the occurrence of explicit requests for euthanasia. Methods Design and study population A prospective cohort study was conducted among cancer patients with an estimated life expectancy of three months or less, between September 1999 and August 2003. The cohort comprised all consecutive cancer patients from the departments of gynecology, medical oncology, lung diseases, and head and neck surgery of the University Medical Center Utrecht in The Netherlands. This 39

Chapter 4

hospital is one of the ten tertiary referral centers for cancer patients in The Netherlands. A patient was eligible for inclusion into the cohort when the attending physician estimated his or her life expectancy to be three months or less, and thought the patient able to participate, i.e., the patient was aware the cancer was untreatable and the patient was able to answer questions regarding depression. Eligible individuals were informed about the study, but the term euthanasia was not explicitly mentioned. Instead the term “medical decisions concerning the end of life” was used, since in practice the physician does not initiate talking about euthanasia: the patient has to bring up the topic. When a patient decided to participate, he or she was asked to sign an informed consent form. We chose to study the association between depressed mood and explicit requests for euthanasia and not actual dying by euthanasia. The reason is that two thirds of all requests are not carried out and in 31% of these non-granted requests (thus 18% of all requests) depression is a reason for the physician not to grant the request (21). We were interested in the relation between depression and requests for euthanasia in patients, regardless of the approval of the physician. The study was approved by the Medical Ethics Committee at the University Medical Center Utrecht. Baseline and follow-up assessments At inclusion into the cohort the participant completed a questionnaire that included a screening instrument for depression: the Hospital Anxiety and Depression Scale (HADS). To diagnose “depressed mood” we used a cut-off score of 20 for the total scale (instead of using two separate scales) on the HADS, as recommended in a palliative setting (22). After inclusion the general practitioner of the patient received a letter with information about the study and an appeal was made to contact the researcher in case of a well considered, persistent request for euthanasia, or if the patient died in a natural way. All physicians from the cooperating departments in the hospital were acquainted with the study and were reminded of participation of their patient by an entry in the medical file. A follow-up measurement was performed when a patient of the cohort explicitly and consistently requested euthanasia, and the euthanasia procedure was started. This implies that the request was discussed in the medical team and a second opinion from an independent physician was obtained. Among these patients and among a randomly selected sample of the rest of the cohort 40


the presence of current and life-time depressive episodes was assessed by the Composite International Diagnostic Interview (CIDI-auto) (23-25). At the moment a case was interviewed, two controls were randomly sampled from the cohort and contacted for an interview. The physicians were blind for the findings of both measurements because we did not want to influence standard care. According to the guidelines for handling euthanasia requests from The Royal Dutch Medical Association a request has to be voluntary, well considered and consistent, but a psychiatric consultation is not mandatory (20). The physician or nurse rated the patient’s functional level on the Karnofsky Performance Status Scale (KPS) after the baseline measurement (26). Scores range from 0 (indicating that the patient has died) to 100 (no functional limitation in activities of daily living). To check whether we missed cases of euthanasia, we obtained information about all distributed euthanatics (Pancuronium dibromine and Thiopental natrium) during the study period from the pharmacy in our hospital. Statistical analyses Two patients had more than 10% missing answers in the HADS questionnaire, these patients were excluded from the analyses concerning depressed mood. When calculating person years follow–up ended at death or April 1, 2004. Relative risks and their 95% confidence interval (CI) were estimated by Cox proportional hazards regression without and with adjustment for age and sex. Analyses were performed using Statistical Package for Social Services Version 11.5 for Windows package (SPSS Inc, Chicago, IL). Results Characteristics and follow-up Between September 1999 and August 2003 198 patients were asked to participate, 40 refused to participate and 18 gave consent but were not able to complete the questionnaire (Figure 1). The cohort consisted of predominantly female patients (64%), the tumor site was mostly gynecological (35.8%) or urological (16.8%) and most patients were hospitalized; 15% filled in the questionnaire at home and returned it by mail. Anti tumor treatment was discontinued at a median period of 2.7 months before inclusion. Eleven patients were still alive at the moment the data were analyzed. Thirty patients (22%) 41

198 patients asked

40 refused

18 not able to complete questionnaire

3 received euthanatics in hospital

30 requested euthanasia

8 died before euthanasia 2 physicians disagreed 1 cause of death unkown

1 CIDI* interview

140 included in cohort, 11 alive April 2004

10 missed interviews researcher not contacted in time

110 without request

19 died by euthanasia: 2 in hospice 7 at home 10 in hospital

11 CIDI interviews

Figure 1 Inclusion into cohort. * Composite International Diagnostic Interview.

4 researcher not contacted in time 2 not feasible 1 refused 1 too ill to cooperate

42 selected for follow up assessment 10 alive April 2004

17 CIDI interviews 2 by telephone 1 with partner

4 refused 1 could not be reached 19 died before interview 1 too ill


from the cohort made an explicit request for euthanasia. Eight of these patients died before the euthanasia was carried out, two times the physician did not agree with the request and one medical file from a hospice got lost, so the actual cause of death is unknown for this person. The remaining nineteen patients died by euthanasia, two in a hospice, seven at home and ten in our hospital (Figure 1). Between September 1999 and August 2003 the pharmacy at the University Medical Center distributed euthanatics 46 times: 12 times to patients included in the study, 3 times to patients who refused, 7 times to patients we missed because the researcher was not informed (especially in the beginning of the study when not all physicians were well acquainted with the study), and 24 times to patients who were not eligible. The main reason patients were ineligible was that they were under treatment by departments not participating in this study (18 times). Table 1 Demographic, tumour, disease and treatment characteristics according to presence or absence of depressed mood. Depressed mood Non depressed mood (n=32) (n=105) Female 18 (56) 70 (67) Age, years 58 (35-81) 60 (22-84) Married or cohabiting, (yes) 22 (69) 72 (67) Children (yes) 24 (75) 77 (73) Religious (yes) 10 (31) 47 (45) Inpatient 27 (84) 89 (85) Tumor site Breast 5 (16) 8 (8) Gastro Intestinal 4 (13) 13 (12) Lung 2 (6) 6 (6) Urological 6 (19) 17 (16) Gynecological 7 (22) 42 (40) Head and Neck 5 (16) 12 (11) Others 3 (9) 7 (7) Functional status (Karnofsky) 51 (30-80) 56 (20-100) Median actual survival after inclusion*, days 34 (2-328) 56 (1-683) Median time since incurable at inclusion, 2.48 (0-28) 2.85 (0-69) months 43

Chapter 4

Depressed mood at inclusion and euthanasia At baseline thirty-two patients (23%) had a depressed mood as assessed by the HADS questionnaire (score > 20 points). Table 1 describes the characteristics of the patients according to presence or absence of depressed mood at inclusion. Fourteen of 32 patients (44%) with depressed mood at inclusion, requested euthanasia during follow-up. Of 105 patients without depressed mood at inclusion 16 (15%) requested euthanasia during follow-up. The risk of a request for euthanasia for patients with a depressed mood was 4.1 (95% confidence interval (CI) 2.0 to 8.5) times higher than that of patients without depressed mood at inclusion (Figure 2). After adjustment for age and sex the relative risk

Figure 2 Time till request euthanasia for depressed and not depressed patients.

44


did not change. In order to assess whether the prevalence of depressed mood increases with shorter life expectancy, which could have been an alternative explanation for our findings, we examined the association between depressed mood and survival among those dying without euthanasia (thus 19 patients were excluded). There was no association between depressed mood and survival, relative risk 1.1 (CI 0.7 to 1.8) (Figure 3).

Figure 3 Survival without euthanasia for depressed and not depressed.

Follow-up measurement of Depressive Disorder by CIDI Twelve of the 30 patients with a request had a follow-up assessment for depression (Figure 1). Fourteen times the researcher was not able to contact the patient since she was not aware that euthanasia was about to take place; in eight of these cases the patient died before euthanasia could have been given. 45

Chapter 4

Two times the interview was not feasible: one patient had aphasia, one was too dazed by morphine. One patient refused the interview because of the distress he was in, one was too ill to cooperate. Forty-two controls were selected for a follow-up assessment. Four refused participation, one could not be reached and nineteen had passed away before the interview could take place (before random selection, those patients known to have died were already excluded) and one was too ill to be interviewed (Figure 1). Seventeen control subjects were interviewed. Two times it was not feasible to visit the patient and in these cases the CIDI was done by telephone or with the partner of the patient. Of the twelve patients that were interviewed after the request for euthanasia was made, the CIDI revealed that two had a Major Depression (one with a mild recurrent episode, the other with a single severe episode) according to DSM-IV criteria at the time of the interview. In addition two persons had a Major Depression within the year before the interview took place. None of the seventeen patients without a request for euthanasia at that moment (controls) were depressed at the time of the interview; two of them had been depressed within the year before the interview took place. Eight persons in the control group suffered from depression at any time in their life, four persons with a euthanasia request suffered from depression at any time in their life. Discussion We performed a prospective cohort study among cancer patients with an estimated life expectancy of three months or less. One fifth of these patients with terminal cancer made an explicit request for euthanasia. Depressed mood (as assessed by the HADS) was associated with a four times increased risk to request euthanasia. Two of twelve patients in whom we assessed current and life time episodes of depression after their explicit request for euthanasia, had a Major Depression, compared to none of the seventeen control patients at the time of the interview. Our study is the first to examine the relation between depressed mood and incidence of euthanasia requests in terminally ill cancer patients. In the protocol for the present study we hypothesized that depressed mood would show an inverse association with requests for euthanasia. Our clinical impression was that such requests are well considered decisions, thoroughly 46


discussed with healthcare workers and family (27). We thought the patients requesting euthanasia were more accepting their impending death and we therefore expected them to be less depressed. To our surprise, we found that a depressed mood was associated with more requests. Two important questions arise. First question is whether it is true that depressed mood is related to requests for euthanasia. To answer it some aspects regarding the design of the study need to be discussed. Firstly, results were based on the questionnaires from 138 patients, leaving out 60 patients that did not want or were not able to participate, most often due to reasons inherent to being terminally ill. As a result the prevalence of depression in this group may have been lower. There is, however, no reason to believe that this would affect the association between depression and euthanasia. Secondly, it may be questioned whether the instruments we used assess depressed mood and depression adequately. The Hospital Anxiety and Depression Scale is not a diagnostic tool but a screening instrument for depression. An advantage of the HADS is that it does not depend on suicidal thoughts, or on symptoms that can also be caused by physical disease. Others have shown that it has a good discriminative ability in a palliative care setting (22). In addition it has recently been demonstrated that the Hospital Anxiety and Depression Scale predicts the development of Major Depression in terminally ill cancer patients (28). Thus it seems reasonable to accept that patients with a score higher than 20 on the HADS may be described as patients with a depressed mood. The Composite International Diagnostic Interview is a structural clinical interview that makes a diagnosis of Major Depression, based on the criteria of the ICD-10 and DSM-IV classification system. It has excellent psychometric properties (23, 25). Unfortunately we did not succeed in assessing depression with the Composite International Diagnostic Interview in a considerable proportion of the patients. Nevertheless the findings from this subgroup do not contradict the findings based on the HADS interview, which was performed in all patients. The prevalence of euthanasia requests in our sample (22%) was comparable with the prevalence of euthanasia requests among cancer patients in the nationwide study: 7,4% died by euthanasia and since only one third of all requests are carried out, it can be expected that 21% did an explicit request (18).

47

Chapter 4

Though the prevalence of euthanasia requests was high, there were several cases of euthanasia in our hospital that were ineligible for this study, mainly because the patients were under treatment at departments not participating in the study. We are not sure if the association between depressed mood and euthanasia will also hold for these patients, who will probably have different types of cancer, or other diseases than cancer. The second question is ‘what are the consequences of the fact that depressed mood is related to requests for euthanasia?’. Treatment of Major Depression in terminally ill patients can be difficult, especially since time is limited. We would urge being vigilant to early detection of depression so that appropriate treatment might be initiated. Psychostimulants have shown to be useful, because of their rapid onset of action (29), and the value of cognitive behavioral treatment in cancer patients has been demonstrated in a prospective randomized trial (30). The question whether a depressed mood can adequately be treated in this terminally ill population and if so, whether or not it would lower the prevalence of requests for euthanasia needs further investigation. The assumption, discussed in the introduction, that a request for euthanasia could be considered as a symptom of a psychiatric disorder can be disputed, since by far not all patients who make a request were found to suffer from Major Depression. The value of a psychiatric consultation as part of the standard procedure for handling euthanasia requests has been studied before (31). It was concluded that standard psychiatrist consultation should not be mandatory, since the benefits should be balanced against the disadvantages and results showed that standard psychiatric evaluation only changed the policy of the primary physician in 9%, though in general staff appreciate the expertise (31). Therefore, we would encourage physicians to consult a psychiatrist whenever they have doubts about whether the depressed mood of a patient affects his or her decision making ability. The disadvantage of mandatory psychiatric evaluation is that it might burden terminally ill patients (32). Since views on assisted suicide in terminally ill patients may also influence clinical opinions of psychiatrists regarding patient competence (32) we think the opinions on this topic may differ for countries outside The Netherlands. The findings suggest that a depressed mood in the last months of life is associated with a higher risk for a request for euthanasia. Replication of these findings in a larger sample and with information on the presence of Major Depression in all patients is needed. 48


Acknowledgements The authors thank all physicians and patients who took part in the study. References 1.

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Zaubler TS, Sullivan MD: Psychiatry and physician-assisted suicide. Psychiatr Clin North Am 1996; 19(3):413-27 Breitbart W: Suicide: Handbook of Psychooncology. Psychological care of the patient with cancer. Edited by Holland JC, Rowland JC. New York, Oxford University Press, 1989, pp 291-299 Chochinov HM, Wilson KG, Enns M, Mowchun N, Lander S, Levitt M, Clinch JJ: Desire for death in the terminally ill. Am.J.Psychiatry 1995; 152(8):1185-1191 Emanuel EJ, Fairclough DL, Daniels ER, Clarridge BR: Euthanasia and physicianassisted suicide: attitudes and experiences of oncology patients, oncologists, and the public. Lancet 1996; 347(9018):1805-10 Breitbart W, Rosenfeld B, Pessin H, Kaim M, Funesti-Esch J, Galietta M, Nelson CJ, Brescia R: Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA 2000; 284(22):2907-2911 Breitbart W, Rosenfeld BD, Passik SD: Interest in physician-assisted suicide among ambulatory HIV-infected patients. Am J Psychiatry 1996; 153(2):238-42 Brown JH, Henteleff P, Barakat S, Rowe CJ: Is it normal for terminally ill patients to desire death? Am.J.Psychiatry 1986; 143(2):208-211 Wilson KG, Scott JF, Graham ID, Kozak JF, Chater S, Viola RA, de Faye BJ, Weaver LA, Curran D: Attitudes of terminally ill patients toward euthanasia and physicianassisted suicide. Arch Intern Med 2000; 160(16):2454-60

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Emanuel EJ, Fairclough DL, Emanuel LL: Attitudes and desires related to euthanasia and physician-assisted suicide among terminally ill patients and their caregivers. Jama 2000; 284(19):2460-8 Tiernan E, Casey P, O'Boyle C, Birkbeck G, Mangan M, O'Siorain L, Kearney M: Relations between desire for early death, depressive symptoms and antidepressant prescribing in terminally ill patients with cancer. J R Soc Med 2002; 95(8):386-90 Kelly B, Burnett P, Pelusi D, Badger S, Varghese F, Robertson M: Factors associated with the wish to hasten death: a study of patients with terminal illness. Psychol Med 2003; 33(1):75-81 Jones JM, Huggins MA, Rydall AC, Rodin GM: Symptomatic distress, hopelessness, and the desire for hastened death in hospitalized cancer patients. J Psychosom Res 2003; 55(5):411-8 Hendin H: Suicide and the Request for Assisted Suicide: Meaning and Motivation. Duquesne Law Review 1996; 35:285-310 Block SD, Billings JA: Patient requests for euthanasia and assisted suicide in terminal illness. The role of the psychiatrist. Psychosomatics 1995; 36(5):445-457 Seale C, Addington-Hall J, McCarthy M: Awareness of dying: prevalence, causes and consequences. Soc.Sci.Med. 1997; 45(3):477-484 Chochinov HM, Tataryn DJ, Wilson KG, Ennis M, Lander S: Prognostic awareness and the terminally ill. Psychosomatics 2000; 41(6):500-504

Chapter 4 17. Hinton J: The progress of awareness and acceptance of dying assessed in cancer patients and their caring relatives. Palliat Med 1999; 13(1):19-35 18. Onwuteaka-Philipsen BD, van der Heide A, Koper D, Keij-Deerenberg I, Rietjens JA, Rurup ML, Vrakking AM, Georges JJ, Muller MT, van der Wal G, van der Maas PJ: Euthanasia and other end-of-life decisions in the Netherlands in 1990, 1995, and 2001. Lancet 2003; 362(9381):395-9 19. Van der Maas PJ, Van Delden JJ, Pijnenborg L, Looman CW: Euthanasia and other medical decisions concerning the end of life. Lancet 1991; 338(8768):66974 20. van der Maas PJ, van der Wal G, Haverkate I, de Graaff CL, Kester JG, Onwuteaka-Philipsen BD, van der Heide A, Bosma JM, Willems DL: Euthanasia, physician-assisted suicide, and other medical practices involving the end of life in the Netherlands, 1990-1995. N Engl J Med 1996; 335(22):1699-705 21. Haverkate I, Onwuteaka-Philipsen BD, van Der Heide A, Kostense PJ, van Der Wal G, van Der Maas PJ: Refused and granted requests for euthanasia and assisted suicide in the Netherlands: interview study with structured questionnaire. BMJ 2000; 321(7265):865-6 22. Le Fevre P, Devereux J, Smith S, Lawrie SM, Cornbleet M: Screening for psychiatric illness in the palliative care inpatient setting: a comparison between the Hospital Anxiety and Depression Scale and the General Health Questionnaire-12. Palliat Med 1999; 13(5):399-407 23. Wittchen HU, Robins LN, Cottler LB, Sartorius N, Burke JD, Regier D: Crosscultural feasibility, reliability and sources of variance of the Composite International Diagnostic Interview (CIDI). The

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Multicentre WHO/ADAMHA Field Trials. Br J Psychiatry 1991; 159:645-53, 658 Peters L, Andrews G: Procedural validity of the computerized version of the Composite International Diagnostic Interview (CIDI-Auto) in the anxiety disorders. Psychol Med 1995; 25(6):1269-80 Andrews G, Peters L: The psychometric properties of the Composite International Diagnostic Interview. Soc Psychiatry Psychiatr Epidemiol 1998; 33(2):80-8 Mor V, Laliberte L, Morris JN, Wiemann M: The Karnofsky Performance Status Scale. An examination of its reliability and validity in a research setting. Cancer 1984; 53(9):2002-2007 Muller MT, Onwuteaka-Philipsen BD, van der Wal G, van Eijk J, Ribbe MW: The role of the social network in active euthanasia and physician-assisted suicide. Public Health 1996; 110(5):271-5 Akechi T, Okuyama T, Sugawara Y, Nakano T, Shima Y, Uchitomi Y: Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors. J Clin Oncol 2004; 22(10):1957-65 Homsi J, Nelson KA, Sarhill N, Rybicki L, LeGrand SB, Davis MP, Walsh D: A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 2001; 18(6):403-7 Greer S, Moorey S, Baruch JD, Watson M, Robertson BM, Mason A, Rowden L, Law MG, Bliss JM: Adjuvant psychological therapy for patients with cancer: a prospective randomised trial. Bmj 1992; 304(6828):675-80 Bannink M, Van Gool AR, van der Heide A, van der Maas PJ: Psychiatric consultation and quality of decision making in euthanasia. Lancet 2000; 356(9247):2067-8

Euthanasia and depression 32. Ganzini L, Leong GB, Fenn DS, Silva JA, Weinstock R: Evaluation of competence to consent to assisted suicide: views of forensic psychiatrists. Am J Psychiatry 2000; 157(4):595-600

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Chapter 5

Who wants euthanasia? A prospective cohort study among terminally ill cancer patients

Marije L. van der Lee Johanna G. van der Bom Nikkie B. Swarte, MD Jan van den Bout Alexander de Graeff A. Peter M. Heintz

Chapter 5

Abstract Background: Euthanasia has been socially accepted and practised in the Netherlands for the last twenty years. Particulars about which patients consider euthanasia and what brings some of them to make an explicit request for euthanasia may improve the quality of care for terminally ill cancer patients. Objective: To study characteristics of cancer patients who consider euthanasia, and to assess determinants of officially requesting euthanasia among patients who considered euthanasia. Design: Prospective cohort study. Setting: The departments of gynecology, medical oncology, lung diseases, and head and neck surgery of the University Medical Center Utrecht, the Netherlands. Patients: 127 consecutive cancer patients with an estimated life expectancy of three months or less. Measurements: Symptom burden (Edmonton Symptom Assessment Scale); depression (Hospital Anxiety and Depression Scale); functional level (Karnofsky Performance Status Scale); demographic and disease characteristics (medical files); information from the general practitioners (self composed questionnaire). Endpoints: Discussing euthanasia with the physician, officially requesting euthanasia. Results: A total of 75 (59%) patients discussed euthanasia with their physician, mostly when the cancer became incurable, or at the end of life. Patients who discussed euthanasia were less often religious. Among patients who had at some point discussed euthanasia, pain was associated with more (odds ratio, 1.37 [95% CI, 1.06 to 1.77]), and being religious was associated with fewer (odds ratio, 0.21 [95% CI, 0.06 to 0.76]) explicit requests for euthanasia. Thirty-two patients made an explicit request and twenty patients died by euthanasia. Conclusions: More than half of all terminally ill cancer patients discuss euthanasia with their physician. Religious patients are less likely to do so. Pain was the most important determinant of explicitly requesting euthanasia among terminally ill cancer patients who previously discussed euthanasia with their physician.

54

Who wants euthanasia?

Introduction Euthanasia has been socially accepted and practised in the Netherlands for the last twenty years. The concern that suboptimal palliative care would urge patients to request euthanasia has prompted several studies in search of reasons or potential predictors of requesting euthanasia. Some have suggested that poor well-being, anxiety and shortness of breath (1, 2), drowsiness (3), poor performance status (4) and feelings of dependency (2, 5, 6) may be associated with requesting euthanasia. Some of the studies suggested that pain may facilitate requesting euthanasia or the wish to hasten death (2, 7-9); yet this was not confirmed in other studies (1, 3, 10, 11). Some studies suggested depression was related with the attitude towards euthanasia (11), while others found no evidence for this relation (1, 3, 12). There is no doubt that predictors for euthanasia are best studied in a country where euthanasia is allowed. From three nationwide studies conducted in the Netherlands among physicians, we know that many patients ask their doctor if they would assist them to die should suffering become unbearable, and that two-thirds of these patients never end up making a serious and persistent request (13-15). It is quite possible that the reasons why patients consider and discuss euthanasia for a later time in the disease, may differ from the factors that bring patients to do an actual explicit request for euthanasia. Although this information is important, since it may improve the quality of care for terminally ill cancer patients, it has not been studied so far. We therefore aimed at describing characteristics of patients considering and discussing euthanasia and at describing which factors predict explicit requests for euthanasia among patients who previously discussed euthanasia. It seems likely that the predictors of requesting euthanasia differ according to the disease that gives rise to the unbearable suffering. Euthanasia is relatively common among terminally ill cancer patients. In the Netherlands about 7.4 percent of cancer patients die by euthanasia (13-15). We therefore focussed on a cohort of terminally ill cancer patients.

55

Chapter 5

Methods Design and study population A prospective cohort study was conducted among cancer patients with an estimated life expectancy of three months or less, between September 1999 and August 2003. The cohort comprised all consecutive cancer patients from the departments of gynecology, medical oncology, lung diseases, and head and neck surgery of the University Medical Center Utrecht in the Netherlands. This center is one of the ten tertiary referral centers for cancer patients in the Netherlands. A patient was eligible for inclusion into the cohort when the attending physician estimated his or her life expectancy to be three months or less, and thought the patient able to participate, i.e., the patient was aware the cancer was untreatable and the patient was able to answer questions regarding psychological and physical well-being and depression. Eligible individuals were informed about the study, but the term euthanasia was not mentioned. Instead the term “medical decisions concerning the end of life” was used, since in practice the physician never initiates talking about euthanasia: the patient has to bring up the topic. When a patient decided to participate, he or she was asked to sign an informed consent form. The study was approved by the Medical Ethics Committee at the University Medical Center Utrecht. Measurements Of each patient the following items were recorded from the medical files (including nurses reports and electronic file information): demographic items (such as gender, religion, marital status, number of children, and age at moment of inclusion), the date of the first diagnosis of cancer and the date the disease became incurable, and whether and when (in what situation) the patient had discussed euthanasia with the specialist. The physician or nurse rated the patient’s functional level on the Karnofsky Performance Status Scale. This scale is widely used to quantify the functional status of cancer patients and is generally considered to be a valuable research tool (16). Scores can range from 100 (no symptoms and no functional limitation in activities of daily living) to 0 (indicating that the patient has died) . Depression was assessed by the Hospital Anxiety and Depression Scale (HADS) (17). To diagnose “depressed mood” we used a cut-off score of 20 for

56


the total scale on the HADS as recommended (18) especially when using it for screening for depression in cancer patients in palliative care . Physical and mental symptom burden were assessed with the Edmonton Symptom Assessment Scale (ESAS), an instrument validated in palliative care settings (19). It has been suggested that among critically ill patients several symptoms are present that are not covered by the items in the original ESAS and that a numerical scale would be better than a visual analogue scale (20). For this study fatigue, sadness, and dependence were added to the ESAS. Each symptom was rated from 0 (“not at all”) to 10 (“very much”). After inclusion the general practitioner of the patient received a letter with information about the study and a short questionnaire to be completed after the patient died, concerning the way of dying and if and when the patient had discussed euthanasia. When the patient had not been seen for a prolonged period, the general practitioner was contacted by telephone to collect information about the patients’ well-being. When the patient passed away and the questionnaire from the general practitioner had not been received, the questionnaire was sent again with a reminder, or the questions were posed by telephone. Statistical analyses Differences between patients who discussed euthanasia and those who did not, were studied and tested by ANOVA’s or two sided Chi squares. Factors potentially related to a request for euthanasia were studied in univariate logistic regression analyses, followed by a multiple regression analysis with all factors that were statistically significant at P < 0.10 in the univariate analyses as independent variables. It has been shown that deleting subjects with a missing value on one of the independent variables leads to biased results (21). Religious affiliation was not indicated in the medical record for 9 patients. The Karnofsky Performance status could not be obtained for 13 patients, mainly because these patients completed their questionnaire at home. Some items from the ESAS were missing for 7 patients. Imputation may partly overcome the bias due to missing data in descriptive research, therefore missing values were imputed using the expectation maximization method (22). The multiple logistic regression analysis was performed before and after imputation.

57

Chapter 5

Results Between September 1999 and July 2003 385 cancer patients noticeably passed the threshold of a life expectancy of 3 months; 187 of these patients were deemed unable to participate in the study by their physician. We asked the remaining 198 patients to participate, and 141 of them participated (Figure 1). No differences in age or gender were found between the patients that participated and those who were not able or refused to participate. 385 pts with life expectancy > 3 months: 198 eligible 17 incomplete questionnaire 141 in cohort, 6 alive

40 refused; reasons: 4 fatigue 6 too ill 8 too distressed 2 no acceptation of being incurable 2 not aware of being incurable 18 other

135 patients 11 no permission to contact GP 14 stayed in hospital last months 14 GP did not react (6 partial info via assistant)

96 GP information, for 6 patients information about discussing euthanasia was unknown

48 discussed euthanasia

32 discussed euthanasia also with specialist

11 did not discuss euthanasia with specialist

39 no information from GP

20 discussed euthanasia with specialist 1 unknown

18 did not discuss euthanasia with specialist

42 did not discuss euthanasia

5 did discuss euthanasia with specialist

30 did neither discuss euthanasia with specialist 7 unknown

Figure 1 Patients included in the cohort who discussed and did not discuss euthanasia. 58


Discussing euthanasia Forty-eight patients (53% of the 90 patients of whom the general practitioner gave information (Figure 1)) discussed euthanasia with their general practitioner and 42 did not, as reported by the general practitioner. Fifty-nine patients discussed euthanasia with their medical specialist as reported in the medical file. Twenty-three patients who did not discuss euthanasia with the medical specialist and for whom information from the general practitioner was missing, because they were mainly under treatment in the hospital and vice versa, were categorized as patients who neither discussed euthanasia with the general practitioner nor with the medical specialist, making one group of 52 patients who did not discuss euthanasia. Fourteen patients were excluded since we did not have enough information to know whether they discussed euthanasia or not. Table 1 presents disease characteristics of the cohort of 127 patients of whom we had complete information. All in all there were 75 patients in our cohort (59%) who discussed euthanasia with either their general practitioner or their medical specialist. Some patients discussed euthanasia when the cancer was first diagnosed, but the majority of patients discussed euthanasia when it became clear the cancer was no longer curable or at the end of life (Table 2). Table 2 Situations in which patients discussed euthanasia for the first time with their general practitioner and/or specialist. N Situation In the last phase of their life 23 The moment it became clear the cancer was no longer curable 21 In a period when they suffered a lot of pain 9 The physician initiated the discussion about euthanasia 5 The moment the cancer recurred 4 The moment the cancer was first diagnosed 4 At the first acquaintance with the physician 2 In a period of depressed mood 2 Other reasons (feeling dependent on medication, physical deterioration, fatigue, difficulty swallowing) 5 Total 75

Table 3 presents characteristics according to whether or not patients discussed euthanasia during follow-up. Gender, marital status, having 59

Chapter 5

children, or age did not differ between patients who discussed euthanasia and patients who did not. Patients who discussed euthanasia were less often religious (43%) than patients who did not discuss euthanasia (64%) (P < 0.05). Table 3. Demographic variables according to discussing and requesting euthanasia. Requested euthanasie, Discussed euthanasia? after discussing it? Yes: n=75 No: n=52 Yes: n=32 No: n=43 n (%) n (%) n (%) n (%) Female Married or cohabiting† Children (none)‡ Religion (yes) § Age, mean (se), years † 1 missing. ‡ 4 missing. § 9 missing.

46 (61) 52 (70) 16 (23) 29 (43) 59 (1.40)

34 (65) 37 (71) 11 (22) 25 (64) 62 (1.80)

21 (66) 21 (68) 7 (23) 9 (32) 58 (2.30)

25 (58) 31 (72) 9 (22) 20 (51) 60 (1.75)

Requesting euthanasia Of all 75 patients who discussed euthanasia, 32 patients (43%) did an explicit request for euthanasia, and 20 (27%) patients actually died by euthanasia. Table 4 presents the relations between somatic and psychological symptoms and explicitly requesting euthanasia among the 75 patients who ever discussed euthanasia. Level of pain, level of insomnia and presence of a depressed mood were positively associated with explicitly requesting euthanasia. Feeling dependent (ESAS), and functional status (Karnofsky) were not related to a request. All variables with a P value of < 0.10 were put in the multivariate model: depression, pain, insomnia and religion. A higher score on pain (range 0 to 10) was an independent predictor for making an explicit request for euthanasia among patients who ever discussed euthanasia (Table 5). Figure 2 presents pain scores (ESAS) according to requesting euthanasia. The effect of pain on requesting euthanasia appeared to be more pronounced among men than among women (Odds Ratio 1.72 (95% confidence interval (CI) 1.15–2.59) and 1.14 (0.90–1.43) respectively. Religion was independently related to a lower risk of making a request for euthanasia among patients who discussed

60


euthanasia (Table 5), which was also more pronounced among women than among men (0.23 (0.07–0.75) and (0.67 (0.16–2.77) respectively (Figure 3). Table 4. Univariate association between potential indicators and request for euthanasia among patients (n=75) who ever discussed euthanasia. Odds ratio 95% CI Somatic symptoms Pain (per point, range 0-10)* (1.07-1.57) 1.30 Drowsiness (per point, range 0-10)* 1.00 (0.86-1.18) Appetite (per point, range 0-10)* 1.09 (0.96-1.24) Shortness of breath (per point, range 0-10)* 1.05 (0.87-1.27) Fatigue (per point, range 0-10)* 1.06 (0.88-1.27) Insomnia (per point, range 0-10)* (1.01-1.37) 1.18 Psychological symptoms Sadness (per point, range 0-10)* 1.12 (0.97-1.29) Anxiety (per point, range 0-10)* (0.90-1.20) 1.04 Well-being (per point, range 0-10)* 1.11 (0.95-1.28) Dependence (per point, range 0-10)* 0.95 (0.82-1.10) Depression (HADS) (score > 20) 3.00 (1.10-8.16) Disease or treatment related Functional status (Karnofsky) (per point, range 0-100) 1.02 (0.99-1.05) Period of disease until incurable, days 0.99 (0.97-1.01) Period of palliative disease, days 0.97 (0.91-1.02) Religion (yes) 0.45 (0. 14-1.13) Odds ratio’s significant at P < .05 are bold. * With each point the patient scores higher the odds ratio increases. Obtained by logistic regression analysis with request for euthanasia as dependent variable. Table 5. Multivariate association with request for euthanasia among patients who ever discussed euthanasia (n =75, Model Nagelkerke R square 0.20). Odds ratio 95% CI Depression (HADS) (score > 20) 1.17 0.34-4.09 Pain (per point, range 1-10)† 1.37 1.06-1.77 Insomnia (per point, range 1-10)† 1.01 0.82-1.23 Religion (yes) 0.21 0.06-0.76 † with each point the patient scores higher the odds ratio increases Obtained by logistic regression analysis with request for euthanasia as dependent variable. 61

Chapter 5

Figure 2 Mean pain scores for male and female patients who did and did not make a request for euthanasia

Discussion Almost 60 percent of all patients with terminal cancer who had a life expectancy of three months or less discussed euthanasia with their physician. The moment the cancer became incurable and the terminal phase of life were situations in which euthanasia was most discussed. Patients who discussed euthanasia were less often religious than patients who did not discuss it. Marital status, age, gender or having children were not related to discussing euthanasia. Of the patients who discussed euthanasia 42 % later explicitly requested euthanasia and 27 % actually died by euthanasia. Among patients who discussed euthanasia, pain was associated with more explicit requests for euthanasia, which was more pronounced among men. Religion was associated 62


with fewer explicit requests for euthanasia in this group, especially for women. Feeling dependent and a worse functional status were not related to making an explicit request among those who discussed euthanasia. We performed a prospective cohort study among cancer patients with an estimated life expectancy of three months or less. This is the first study in a country where euthanasia is regulated, that has studied symptoms related to an explicit request for euthanasia among patients that previously considered and discussed it. Symptoms were reported by the patients themselves, before the patient or the researcher knew if the patient would later request for euthanasia. Before interpreting these results we need to consider possible limitations of the study. We restricted inclusion to patients who were aware of their limited life expectancy and were able to answer questions regarding physical and mental well-being. Therefore, the group may represent a relatively ‘fit’ selection of all patients dying from cancer. The mean age, marital status, number of children and prevalence of religion in our study was similar to that of previous samples of cancer patients who were selected randomly from a database of all cancer patients that died in our hospital (23). In addition, we may have misclassified some of the twenty-three patients of whom information about discussing euthanasia was missing. We classified them as patients who neither discussed euthanasia with the general practitioner nor with the medical specialist, while we had only limited information about these patients. Half of them did not want the researcher to obtain information from the general practitioner, mostly because their relationship with their general practitioner was bad. In these cases we can be reasonably sure that the patient would discuss his possible consideration of euthanasia with the medical specialist and not with the general practitioner. The remaining patients stayed in a nursing home or hospice for the last months of life and had very little, to no contact with the general practitioner or medical specialist. Because euthanasia occurs rarely in nursing homes (24), and it is known that most hospices do not have a benevolent attitude towards euthanasia, it is likely that most patients who do consider euthanasia discuss this with their physician before going to the hospice or nursing home. The percentages of people discussing (59%) and requesting (22%) euthanasia in our study, do agree with what would be expected based on the nation wide studies: 7% of all cancer deaths are by euthanasia, and since two thirds of all patients discussing euthanasia do not come to make an explicit request and only one third of all 63

Chapter 5

explicit requests is carried out (13-15), this would imply that 21% of all cancer patients explicitly request euthanasia and 63% discuss euthanasia. Previous findings suggested the following demographic features to be positively related with the attitude towards euthanasia: lack of religious beliefs (1, 3, 9), male sex (1), younger age (9), not being married and not having children (6), although some findings suggested no relation with age (1, 3, 6) and gender (3, 6). Our results only confirm the role of religion. The difference in findings may be due to the differences between the study populations, e.g. the distribution of primary tumor sites varies over studies, and some of the studies have heterogeneous groups with respect to the diagnosis giving rise to the unbearable suffering (5, 6, 9), or to the fact that attitudes toward euthanasia differ in countries where euthanasia is prohibited. Apart from depression, insomnia and pain we found no relation between somatic or psychological symptoms that have previously been found to be related to euthanasia (1-4), (5, 6). In this context it is important to note that we were the first to study symptoms related to an explicit request for euthanasia among patients that previously considered and discussed it. Since some patients would never choose euthanasia, because of religious grounds for example, it is interesting to study what leads to euthanasia among those who do consider it. This way of analyzing also gives information about why many patients who consider euthanasia, do not come to make an explicit request. Religion prevents patients from discussing euthanasia, and religion prevents those who did previously discuss euthanasia from making an explicit request. Patients who do not experience a lot of pain are also less likely to make an explicit request although they have considered and discussed euthanasia. Previously we reported that depressed mood was related to a four times greater risk to request for euthanasia (25), independent of pain or religion. Moreover, pain did not have a strong association with the risk for an explicit request for euthanasia in the whole group. In the group of patients that already discussed euthanasia the association between depression and an explicit request for euthanasia diminished after adjustment for pain. This suggests that among the patients who consider and discuss euthanasia, the intensity of pain adds to the decision of making an explicit request. Moreover, we found that the relation between pain and an explicit euthanasia request was more pronounced among men. Perhaps in previous studies, which yielded inconsistent results regarding the influence of pain (1-3, 10, 26), the role of pain varied with the 64


number of men in the study and with the outcome: considering euthanasia, or making an explicit request. Although we assessed pain only at one moment in time, still a clear relation with an explicit request for euthanasia, among those who discussed euthanasia, was found. This finding is in line with a previous study where pain was found to be reported more frequently in the files of patients who died by euthanasia, than in those who did not die by euthanasia (23). If we take the stance that pain should not lead to euthanasia, then the results of this study suggest that patients who consider euthanasia, need better pain relief. In advanced cancer patients, pain is treated by utilizing the analgesic ladder proposed by the World Health Organization, which ends with opioids (27). However, opioids have the side effect of making people drowsy, and some people wish to take leave in full conscience. Terminal sedation is no option for them. The development or better availability of ways of pain relief that do not make people drowsy, might be of help to them. Women are in general more sensitive to pain (28) and have more experience with pain, so they may have learned to cope with pain better than men (29). Our findings suggest that many cancer patients, regardless of gender, marital status, or parental status, discuss euthanasia with their physician as they become incurably or terminally ill. Especially for men who consider euthanasia, pain adds to the decision of making an explicit request; while religion seems to prevent, particularly women, who consider euthanasia, to do an explicit request. Feeling dependent or being dependent (i.e. a worse functional status) were not related to making an explicit request among those who discussed euthanasia. References 1.

2.

Suarez-Almazor ME, Newman C, Hanson J, Bruera E. Attitudes of terminally ill cancer patients about euthanasia and assisted suicide: predominance of psychosocial determinants and beliefs over symptom distress and subsequent survival. J Clin Oncol. 2002;20(8):2134-41. Morita T, Sakaguchi Y, Hirai K, Tsuneto S, Shima Y. Desire for death and requests 65

3.

4.

to hasten death of Japanese terminally ill cancer patients receiving specialized inpatient palliative care. J Pain Symptom Manage. 2004;27(1):44-52. Wilson KG, Scott JF, Graham ID, et al. Attitudes of terminally ill patients toward euthanasia and physician-assisted suicide. Arch Intern Med. 2000;160(16):2454-60. Akechi T, Okamura H, Yamawaki S, Uchitomi Y. Why do some cancer patients

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5.

6. 7.

8.

9.

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with depression desire an early death and others do not? Psychosomatics. 2001;42(2):141-5. Sullivan AD, Hedberg K, Fleming DW. Legalized physician-assisted suicide in Oregon--the second year. N Engl J Med. 2000;342(8):598-604. Wineberg H, Werth JL, Jr. Physicianassisted suicide in Oregon: what are the key factors? Death Stud. 2003;27(6):501-18. Meier DE, Emmons CA, Litke A, Wallenstein S, Morrison RS. Characteristics of patients requesting and receiving physician-assisted death. Arch Intern Med. 2003;163(13):1537-42. Virik K, Glare P. Requests for euthanasia made to a tertiary referral teaching hospital in Sydney, Australia in the year 2000. Support Care Cancer. 2002;10(4):30913. Emanuel EJ, Fairclough DL, Emanuel LL. Attitudes and desires related to euthanasia and physician-assisted suicide among terminally ill patients and their caregivers. Jama. 2000;284(19):2460-8. Sullivan M, Rapp S, Fitzgibbon D, Chapman CR. Pain and the choice to hasten death in patients with painful metastatic cancer. J Palliat Care. 1997;13(3):18-28. Emanuel EJ, Fairclough DL, Daniels ER, Clarridge BR. Euthanasia and physicianassisted suicide: attitudes and experiences of oncology patients, oncologists, and the public. Lancet. 1996;347(9018):1805-10. Pacheco J, Hershberger PJ, Markert RJ, Kumar G. A longitudinal study of attitudes toward physician-assisted suicide and euthanasia among patients with noncurable malignancy. Am J Hosp Palliat Care. 2003;20(2):99-104. Onwuteaka-Philipsen BD, van der Heide A, Koper D, et al. Euthanasia and other end-of-life decisions in the Netherlands in

14.

15.

16.

17. 18.

19.

20.

21.

22.

1990, 1995, and 2001. Lancet. 2003;362(9381):395-9. Van der Maas PJ, Van Delden JJ, Pijnenborg L, Looman CW. Euthanasia and other medical decisions concerning the end of life. Lancet. 1991;338(8768):66974. Van der Maas PJ, van der Wal G, Haverkate I, et al. Euthanasia, physicianassisted suicide, and other medical practices involving the end of life in the Netherlands, 1990-1995. N Engl J Med. 1996;335(22):1699-705. Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale. An examination of its reliability and validity in a research setting. Cancer. 1984;53(9):2002-2007. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-70. Spinhoven P, Ormel J, Sloekers PP, Kempen GI, Speckens AE, Van Hemert AM. A validation study of the Hospital Anxiety and Depression Scale (HADS) in different groups of Dutch subjects. Psychol Med. 1997;27(2):363-70. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991;7(2):6-9. Rees E, Hardy J, Ling J, Broadley K, A'Hern R. The use of the Edmonton Symptom Assessment Scale (ESAS) within a palliative care unit in the UK. Palliat Med. 1998;12(2):75-82. Oostenbrink R, Moons KG, Bleeker SE, Moll HA, Grobbee DE. Diagnostic research on routine care data: prospects and problems. J Clin Epidemiol. 2003;56(6):501-6. Greenland S, Finkle WD. A critical look at methods for handling missing

Who wants euthanasia? covariates in epidemiologic regression analyses. Am J Epidemiol. 1995;142(12):1255-64. 23. Swarte NB. Euthanasia among hospitalised cancer patients and the consequenses for the bereaved. Utrecht University; 1999. 24. Van der Wal G, Muller MT, Christ LM, Ribbe MW, van Eijk JT. Voluntary active euthanasia and physician-assisted suicide in Dutch nursing homes: requests and administration. J Am Geriatr Soc. 1994;42(6):620-3. 25. Van der Lee M, van der Bom, JG, Swarte, NB, Heintz APM, de Graeff, A, van den Bout J. Euthanasia and depression, a

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prospective cohort study among terminally ill cancer patients. submitted. 2004. Emanuel EJ. Euthanasia and PhysicianAssisted Suicide. Arch Intern Med. 2002;162(jan 28):142-152. WHO. (World Health Organization). Cancer pain relief and palliative care. 1990. Berkley KJ. Sex differences in pain. Behavioral & Brain Sciences. 1997;20(3):371380. Unruh AM, Ritchie J, Merskey H. Does gender affect appraisal of pain and pain coping strategies? Clin J Pain. 1999;15(1):31-40.

PART II

EUTHANASIA AND OTHER FACTORS RELATED TO COMPLICATED GRIEF IN THE RELATIVES

Chapter 6

Euthanasia: effects on the bereaved. A cross-sectional study

Nikkie B. Swarte Marije L. van der Lee Johanna G. van der Bom Jan van den Bout A. Peter M. Heintz

Chapter 6

Abstract Objective: To assess how euthanasia in terminally ill cancer patients affects the grief response of bereaved family and friends. Design: Cross sectional study. Setting: A tertiary referral centre for oncology patients in Utrecht, the Netherlands. Participants: 189 bereaved family members and close friends of terminally ill cancer patients who died by euthanasia and 316 bereaved family members and close friends of comparable cancer patients who died a natural death between 1992 and 1999. Main outcome measures: Symptoms of traumatic grief assessed by the Inventory of Traumatic Grief, current feelings of grief by the Texas revised inventory of grief, and posttraumatic stress reactions by the impact of event scale. Results: The bereaved family and friends of cancer patients who died by euthanasia had less traumatic grief symptoms (adjusted difference -5.29 (95% confidence interval -8.44 to -2.15)); less current feeling of grief (adjusted difference was 2.93 (0.85 to 5.01)); and less posttraumatic stress reactions (adjusted difference was -2.79 (-5.33 to -0.25)) than the family and friends who died of natural causes. These differences were independent of other risk factors. Conclusions: The bereaved family and friends of cancer patients who died by euthanasia coped better with respects to grief symptoms and posttraumatic stress reactions than the bereaved of comparable cancer patients who died a natural death. These results should not be interpreted as a plea for euthanasia, but as a plea for the same level of care and openness in all patients who are terminally ill. Introduction Grief is a normal reaction to the death of a loved one and normally does not require any professional help. Traumatic grief refers to the situation where grief symptoms take too long or too short, are too intense or not intense enough, or come too late.1 Depending on the definition, 10-20% of bereaved people will suffer from traumatic grief. Sudden loss, loss of a child or a partner, low self-esteem, low internal control, lack of religion or spiritual belief, lack of social support, low education 72

Euthanasia: effects on the bereaved

and young age have been identified as risk factors for developing traumatic grief.2 Unnatural death, such as suicide, can cause severe grief reactions in family members.3 As euthanasia is also considered as an unnatural death, it has been suggested that euthanasia may induce traumatic grief. 3 However, the grief experienced by family members in suicide cases differs from grief after euthanasia, mainly because the relatives of the latter have had the opportunity to say goodbye, which is seldom the case in suicides.4 Physician-assisted suicide should be expected to resemble euthanasia on this point, because it will also usually be announced. In the Netherlands euthanasia is carried out on about 3200 persons per year, of whom 80% have cancer.5;6 So far, no studies have been made of how euthanasia in terminally ill cancer patients affects their bereaved family and friends.7 The aim of this study was to examine the effects of euthanasia in terminal cancer patients on grief among bereaved family and friends. Participants and methods Study Population We conducted a cross-sectional study among the bereaved families and friends of cancer patients who had died, either by euthanasia or natural causes, in the University Medical Centre Utrecht between 1992 and 1999. Euthanasia was defined as “the intentional termination of the life of a patient at his or her request by a physician”.6;8 This definition excludes termination of life without the request of the patient, as well as alleviation of pain and other symptoms with medication that finally hastens the patient’s death. All patients who died by euthanasia in our hospital during 1992–9 were centrally registered and we selected them as patients for our study. For each patient who died by euthanasia we selected two control patients from all cancer patients who died from natural causes in our hospital during the same period. To achieve comparability between these groups, we matched control patients by age of death, by year of death, and by sex. During 1992-9, 95 patients died by euthanasia in the University Medical Centre Utrecht, of whom89 were oncology patients. We were unable to contact the bereaved family and friends of11 of these 89 patients because of incorrect mailing addresses, leaving 78 patients in the study. We therefore selected 156 control patients from the 1360 oncology patients who died naturally in our hospital during the same period. 73

Chapter 6

The study population consisted of bereaved people who were immediate family members (partner, parent, child, or sibling) or friends who were with the patient at the moment of death, were informed about the cause of death, were aged 18-85 years, and were fluent in Dutch. The physicians of the deceased patients approached the family members through the persons who were registered as contact names in the medical files. These contacts were asked to participate in this study and to supply the names and addresses of the other immediate family members and of relatives and friends who were with the patient at the moment of death so these individuals could also be approached. We sent a questionnaire to all potential participants a week after sending them a letter giving information on out study. We sent a non-response form with the questionnaire and to those who did not respond, we sent a reminder a month after sending the questionnaire. Measurements Between January 2000 and August 2001 questionnaires were sent to all participants. The questionnaire contained, beside demographic items, seven standardised questionnaires assessing grief symptoms, post-traumatic stress reactions, general wellbeing, depressive symptoms and personality; ass well as a general questionnaire we composed about several aspects of the period of the patients death. We assessed grief with a Dutch version of the inventory of traumatic grief (ITG) 9 , a 29 item, self completed questionnaire with a high score indicating a greater risk for traumatic grief, and with the second subscale of the Texas revised inventory of grief (TRIG), which consists of 13 items and measures current reactions to loss with high scores representing less current grief symptoms.10 The total score of the ITG, representing traumatic grief symptom severity, is calculated by the summation of the 29 item scores with a high score indicating a greater risk for traumatic grief. The TRIG consisted of 13 items with high scores representing less current grief symptoms. In this crosssectional study we used this second subscale of the TRIG because we were interested in the symptoms and psychological distress at the moment of the measurement, avoiding any recall bias. Posttraumatic stress reactions related to the dying process of a beloved person were measured by the Impact of Event Scale (IES) and can be divided into the subscales intrusion and avoidance.11 A high score on the IES reflected 74


more posttraumatic stress reactions. General well-being was assessed by the Symptom Check List (SCL-90), which is a 90-item self-report symptom inventory designed to measure psychiatric symptomatology.12 A high score on the SCL-90 indicated less general well-being. Depressive moods were assessed by a Dutch version of the Depressive Adjective Checklist (DACL).13 This assessment tool consisted of 22 “positive” words and 12 “negative” words. The total score was the number of marked “negative” words together with the number of unmarked “positive” words and a high score indicated more depressive symptoms. The personality of family members was assessed by the Generalised SelfEfficacy Scale (SES)14, which measures self-confidence, and by the Eysenck Personality Questionnaire (EPQ-RRS)15, of which we used the part that measured neuroticism. The self-composed general questionnaire contained questions like “Do you think you have really been able to say goodbye to the patient?” with answers on a five point scale ranging from ‘not at all’ to ‘yes completely’. Another question concerned support from others “Do you think you have received enough support from others after the death?” Furthermore, the medical files of the patients who died by euthanasia and of the matched cancer patients who died naturally were reviewed. The following characteristics of these patients were documented: 1) demographic characteristics, 2) medical history, and 3) symptoms and treatment during their last admission. The duration of illness was defined as the period in months between date of cancer diagnosis and date of death. The cancer was defined as untreatable at the time (i.e. date of untreatable cancer) no curative options were left for the treatment of the disease. Power calculation and statistical analysis Our primary end point was the Inventory of Traumatic Grief. Calculation with an estimated mean on the ITG of 53 with a standard deviation of 20 for the relatives of patients who died a natural death, we would need 300 relatives of patients who died a natural death and 150 relatives of patients who died with euthanasia, to find, with a power of 0.90 and a 2-sided significance of 0.05, a 10% increased or decreased score for the relatives of patients who died with euthanasia. We therefore decided to try to contact the relatives of all 78 patients who died by euthanasia between 1992 and 1999 and to contact the relatives of twice as many patients who died a natural death. 75

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The p values shown in Table 2 were not derived from the multilevel analysis but from either the Pearson χ² test for discrete characteristics or from a T-test. Multilevel analysis was performed with the software program MLwiN 1.1.16 This statistical technique allowed for the dependency of measurements in hierarchically structured data whereas traditional multiple regression analysis presupposes the independency of observations. That is, there is a positive correlation between responses from family members/close friends associated with the same deceased person. Grief symptoms, posttraumatic stress reactions, general well-being, and depressive symptoms were considered as continuous outcomes. When a questionnaire had more than 10% of the values missing, it was not included in the analyses. For the other missing values, the mean values of the study population were used. Results The presented findings are based on returned questionnaires of the bereaved of 58 of all 78 patients who died by euthanasia and 114 of the 156 patients who died naturally. Table 1 presents the characteristics and medical history of the deceased patients according to cause of death. Due to the matching procedure, no apparent difference in age of death, year of death (described by the period between the questionnaire and date of death), and gender of the patients who died or did not die by euthanasia was present. The duration of illness appeared somewhat longer for the patients who died by euthanasia than for those who did not. There was no difference in whether or not the cancer was untreatable at first diagnosis. In total, 264 questionnaires were sent to the bereaved of cancer patients who died by euthanasia, i.e., “the bereaved of euthanasia death”. One hundred ninety-seven questionnaires (74.6%) were filled in, of which 189 (71.5%) had less than 10% missing values. The questionnaire was sent to 480 bereaved persons of cancer patients who died from natural causes, i.e., “the bereaved of natural death”. Three hundred thirty-two (69%) were filled in, of which 316 (66%) had less than 10% missing values. The family members who did not complete the (whole) questionnaire or did not respond were more likely to be male (51%) as compared to those who responded (43% male) and they did not differ in their kind of kinship with the deceased.

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Table 1 Characteristics and medical history of 58 cancer patients who died from euthanasia in the University Medical Center Utrecht between 1992 and 1999 and 114 control cancer patients who died from natural causes. Values are numbers (percentages) unless specified otherwise. Cause of death Euhanasie Natural death (n=58) (n=114) Female 37/58 (64) 70/114 (61) Mean (95% CI) age of death, years 61 (58-64) 62 (60-64) Geometric mean (95% CI) length of illness, months 15 (10-22) 10 (7-13) Cancer untreatable at first diagnosis 8/58 (14) 23/114 (20) Geometric mean (95% CI) between date questionnaire sent out and date of death, months 35 (29-43) 39 (34-43)

Table 2 presents the demographic characteristics of the bereaved of the euthanasia and natural death groups. The bereaved of euthanasia death were shown to be less religious compared to the bereaved of natural death. The kinship with the patients differed between both groups: the bereaved of euthanasia death consisted more of the subgroup defined as others (like cousins, in-laws or friends) and the bereaved of natural death consisted of more children and siblings. The level of education was higher in the bereaved of euthanasia death than the bereaved of natural death. Table 3 shows the crude and adjusted differences in grief symptoms, posttraumatic stress reactions, general well-being and depressive symptoms between the bereaved of euthanasia and natural death. For all questionnaires except for the TRIG a high score means more symptoms and/or complaints. A small, but not significant, difference was noticed on the SCL-90 between the groups; the bereaved of euthanasia death scored somewhat higher on general well-being. The bereaved of both groups scored similarly on the DACL. However, the bereaved of euthanasia death had lower scores on the ITG and higher scores on the TRIG than the bereaved of natural death group. Additionally, the IES score was lower in the bereaved of euthanasia death. In the control group twice as many people (respectively 5.7% versus 2.1%) fulfilled the criteria of traumatic grief, this indicates that there is not only a statistically but also a clinically significant difference. Educational level of the bereaved, the outcome of the bereaved on the EPQ neuroticism scale, and kinship were considered as the most important 77

Chapter 6

Table 2 Demographic characteristics of the relatives and friends of 58 cancer patients who died from euthanasia in the University Medical Center Utrecht between 1992 and 1999 and 114 control cancer patients who died from natural causes. Values are numbers (percentages) unless specified otherwise. Cause of death Euthanasia Natural death p value of (n=189) (n=316) difference Female 102/189 (54) 184/316 (58) 0.4 Mean (SD) age, years 48 (14) 49 (14) 0.4 Religious 89/184 (48) 200/313 (64) 0.01 Relationship with dead patient Spouse 33/189 (17) 61/316 (19) Parent 4/189 (2) 4/316 (1) Offspring 56/189 (30) 117/316 (37) 72, according to Dutch norm scores) and 13 (15%) scored in the lowest range (< 52) of cohesion. Most relatives indicated that the functioning of the family had not changed (25%), or slightly changed (42%) by the disease of their family member. Predictors of grief Table 2 presents the results of univariate and multivariate Multilevel regression analyses with all predictors on complicated grief. Contrary to our hypotheses, depression in patients was not related to grief in the relatives. Neither was full open awareness related to complicated grief. High cohesion predicted complicated grief in the univariate analysis, but in the multivariate analysis with the variable ‘being the partner’ there was no significant relation between cohesion and grief. In the univariate as well as the multivariate model, partners, relatives who scored higher on avoidance (pre-bereavement), relatives who were more neurotic (pre-bereavement) and female relatives had higher scores on complicated grief after the loss. The strongest predictor was being the partner of the patient, followed by avoidance and then neuroticism (comparing the standardized regression coefficients in Table 2). These predictors together predicted 47% of the variance in complicated grief. Discussion Being the partner of the patient, avoidance of feelings and thoughts about the information that the disease of their loved one could not be cured, neuroticism and female gender were important predictors of complicated grief among relatives of adult terminally ill cancer patients. These variables together predicted 47% in the variance of complicated grief. High family cohesion predicted complicated grief in this prospective study, though only in a univariate analysis and not when being the partner was controlled for. Obviously being the partner is easier to assess than family cohesion, and partnership was also a stronger predictor than family cohesion. Whether the relative talked with the patient about impending death or not did not predict complicated grief, neither did depression of the patient.

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Prediction of complicated grief

Table 2 Predictors of grief in univariate and multivariate multilevel regression analysis (N = 55 patients, N = 237 observations). Complicated grief Univariate analysis Multivariate analysis B SE ß* B SE ß* Shared patient level Age, years -0.40 0.15 -0.16 0.18 0.12 0.10 Depression (yes) 4.05 3.86 Karnofsky -0.11 0.09 Discussed euthanasia -3.50 3.14 Period of palliative disease, days -0.20 0.13 Religion 3.7 2.8 Female (yes) -3.47 3.09 Individual relative level Full open awareness -3.04 3.01 Awareness time -1.23 0.83 4.64 Female (yes) 5.12 2.85 0.14 2.24 0.13 Education -1.19 0.82 Age (years) 0.12 0.10 Religion (yes) 1.73 2.94 Children (number) 1.61 3.13 0.95 Neuroticism 1.76 0.45 0.30 0.38 0.16 19.58 Being the partner 19.37 2.92 0.44 2.58 0.44 Cohesion (N = 170) 0.39 0.18 0.19 0.07 0.17* 0.03 0.51 Avoidance 0.80 0.20 0.35 0.14 0.22 Time level Time, months -1.61 0.21 -1.63 0.21 The factor time was included in all univariate analyses. * The ß reflects the standardized regression coefficient. † This analysis was done separately because of the lower N, in this analysis the effect of cohesion on grief was controlled for being the partner of the patient or not. B’s significant at P < 0.05, in the multivariate model are printed bold

The predictive value of awareness, family cohesion, depression in patients and neuroticism and avoidance for complicated grief in relatives of cancer patients, have not been assessed simultaneously and pre-bereavement in earlier studies. Since it has been demonstrated that supporting spouses or children during the terminal illness is more important than support post-loss [4], we 95

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think our results are important for recognizing those relatives who might need extra support during the terminal illness of the patient. Furthermore previous studies have not often included several relatives per patient. Several methodological issues are important to note. Since we had to ask permission from patients before approaching their family members, a selection bias in our sample may have occurred. The patients may have made a selection of relatively healthy family members of whom they thought able to answer questions regarding to coping with a severely ill relative, although we always asked for as many relatives as possible. Consequently full open awareness among relatives in this sample may have been somewhat higher than in the general population of relatives of cancer patients. Another limitation may have been the way we assessed full open awareness. Where previous studies used qualitative interviews, we tried to assess full open awareness with two questions. The validity of these questions has not been assessed yet. It is worthwhile to try to study awareness quantatively, at the same time it is hard to assess it in a direct way. A study wherein the general practitioners would judge the level of awareness would be highly interesting, since that would be an indirect, quantitative assessment. In addition, general practitioners have to be able to assess the predictors, because they have to refer high risk family members in practice. Since we could not compare partners to parents, or children younger than 15 years, our results only show that partners are more affected than siblings, adult children and second degree relatives. From previous studies we know that parents are also at a high risk [39]. Our finding that depression was not related to complicated grief was contrary to expectations based on previous findings [5-7]. In our study the end point was complicated grief, a disorder distinct from depression that has been said to be more prevalent after a bereavement event [2]. We did find that depression in patients was related to depression in relatives (unreported results), but depression in patients was not related to complicated grief. Moreover previous studies did not assess depression or distress in patients themselves but relied on the perceived depression or distress by the relative, which may be a better predictor of grief in the relatives. Our finding that avoidance is related to complicated grief is complementary to the finding that among bereaved caregivers of men with AIDS, those that had relied on avoidance coping strategies reported the most suicidal ideation 96

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[25] and distancing pre-bereavement was associated with depression after the loss [26]. Since other studies demonstrated that avoidance strategies may prolong and intensify distress following loss [23-26], it would be interesting to study whether intervening on avoidance strategies in high risk relatives before the loss, would prevent the development of complicated grief. Although the disease of the patient often affects a whole family, and familycentered care is a desired goal in palliative care [40], we think the merits of family focused interventions need to be empirically tested against the merits of interventions targeted at individual relatives at high risk, since partners of cancer patients were obviously at higher risk of developing complicated grief than siblings, adult children and other relatives. One argument in favor of a clinical approach that screens for families rather than individuals at high risk was that greater levels of psychosocial morbidity were present in families whose functioning as a group was poorer [20]. However, this does not say much about the efficiency of a family focused approach in comparison with an intervention targeted only at the partners. Future research should focus on the relative efficacy of both types of intervention. We suggest that partners, relatives who engage in avoidance strategies after hearing the cancer of their loved one is incurable, and relatives who are more neurotic, would seem most likely to benefit from support, since these relatives were at the highest risk for developing complicated grief after the death of the patient. Interventions may be targeted at the avoidance strategies. Acknowledgements The authors thank all relatives and patients who took part in the study. This study is supported by a grant from the Research Institute for Psychology and Health, and by the Department of Gynecology, University Medical Center Utrecht. The author(s) declare that they have no competing interest. References 1.

CJ Murray, AD Lopez: Mortality by cause for eight regions of the world: Global

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GK Silverman, JG Johnson, HG Prigerson: Preliminary explorations of the effects of prior trauma and loss on risk for psychiatric disorders in recently widowed people. Isr J Psychiatry Relat Sci 2001, 38:202-15. 3. WG Lichtenthal, DG Cruess, HG Prigerson: A case for establishing complicated grief as a distinct mental disorder in DSM-V. Clin Psychol Rev 2004, 24:637-62. 4. DM Bass, K Bowman, LS Noelker: The influence of caregiving and bereavement support on adjusting to an older relative's death. Gerontologist 1991, 31:32-42. 5. ME Kurtz, JC Kurtz, CW Given, B Given: Relationship of caregiver reactions and depression to cancer patients' symptoms, functional states and depression--a longitudinal view. Soc Sci Med 1995, 40:837-46. 6. U Valdimarsdottir, AR Helgason, CJ Furst, J Adolfsson, G Steineck: The unrecognised cost of cancer patients' unrelieved symptoms:a nationwide follow-up of their surviving partners. Br J Cancer 2002, 20;86:1540-1545. 7. HG Prigerson, E Cherlin, JH Chen, SV Kasl, R Hurzeler, EH Bradley: The Stressful Caregiving Adult Reactions to Experiences of Dying (SCARED) Scale: a measure for assessing caregiver exposure to distress in terminal care. Am J Geriatr Psychiatry 2003, 11:309-19. 8. C Seale, J Addington-Hall, M McCarthy: Awareness of dying: prevalence, causes and consequences. Soc.Sci.Med. 1997, 45:477-484. 9. HM Chochinov, DJ Tataryn, KG Wilson, M Ennis, S Lander: Prognostic awareness and the terminally ill. Psychosomatics 2000, 41:500-504. 10. A van der Heide, L Deliens, K Faisst, T Nilstun, M Norup, E Paci, G van der Wal,

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PJ van der Maas: End-of-life decisionmaking in six European countries: descriptive study. Lancet 2003, 362:345-50. E Shapiro: Grief in interpersonal perspective: theories and their implications. In: Handbook of bereavement research: Consequences, coping and care Edited by MS Stroebe, RO Hansson, W Stroebe, HAW Schut. pp. 301-321. Washington: American Psychological Association Books; 2001: 301-321. M Cleiren, RF Diekstra, AJ Kerkhof, J van der Wal: Mode of death and kinship in bereavement: focusing on "who" rather than "how". Crisis 1994, 15:22-36. E Schoka Traylor, B Hayslip, Jr., PL Kaminski, C York: Relationships between grief and family system characteristics: A cross lagged longitudinal analysis. Death Studies 2003, Vol 27:575-601. GI Ringdal, MS Jordhoy, K Ringdal, S Kaasa: Factors affecting grief reactions in close family members to individuals who have died of cancer. J Pain Symptom Manage 2001, 22:1016-26. J Hinton: Whom do dying patients tell? Br Med J 1980, 281:1328-30. KM BrintzenhofeSzoc, ED Smith, JR Zabora: Screening to predict complicated grief in spouses of cancer patients. Cancer Pract. 1999, 7:233-239. DW Kissane, S Bloch, DL Dowe, RD Snyder, P Onghena, DP McKenzie, CS Wallace: The Melbourne Family Grief Study, I: Perceptions of family functioning in bereavement. Am J Psychiatry 1996, 153:650-8. DW Kissane, S Bloch, P Onghena, DP McKenzie, RD Snyder, DL Dowe: The Melbourne Family Grief Study, II: Psychosocial morbidity and grief in bereaved families. Am J Psychiatry 1996, 153:659-66.

Prediction of complicated grief 19. DW Kissane, DP McKenzie, S Bloch: Family coping and bereavement outcome. Palliat.Med. 1997, 11:191-201. 20. DW Kissane, M McKenzie, DP McKenzie, A Forbes, I O'Neill, S Bloch: Psychosocial morbidity associated with patterns of family functioning in palliative care: baseline data from the Family Focused Grief Therapy controlled trial. Palliat Med 2003, 17:527-37. 21. JA Hunfeld, JW Wladimiroff, J Passchier: The grief of late pregnancy loss. Patient Educ Couns 1997, 31:57-64. 22. W Middleton, B Raphael, P Burnett, N Martinek: Psychological distress and bereavement. J Nerv Ment Dis 1997, 185:447-53. 23. PA Boelen, J van den Bout, MA van den Hout: The role of negative interpretations of grief reactions in emotional problems after bereavement. J Behav Ther Exp Psychiatry 2003, 34:225-38. 24. S Nolen-Hoeksema, A McBride, J Larson: Rumination and psychological distress among bereaved partners. J Pers Soc Psychol 1997, 72:855-62. 25. C Rosengard, S Folkman: Suicidal ideation, bereavement, HIV serostatus and psychosocial variables in partners of men with AIDS. AIDS Care 1997, 9:373-84. 26. S Folkman, M Chesney, L Collette, A Boccellari, M Cooke: Postbereavement depressive mood and its prebereavement predictors in HIV+ and HIV- gay men. J Pers Soc Psychol 1996, 70:336-48. 27. AS Zigmond, RP Snaith: The hospital anxiety and depression scale. Acta Psychiatr Scand 1983, 67:361-70. 28. P Le Fevre, J Devereux, S Smith, SM Lawrie, M Cornbleet: Screening for psychiatric illness in the palliative care inpatient setting: a comparison between the Hospital Anxiety and Depression Scale

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and the General Health Questionnaire-12. Palliat Med 1999, 13:399-407. V Mor, L Laliberte, JN Morris, M Wiemann: The Karnofsky Performance Status Scale. An examination of its reliability and validity in a research setting. Cancer 1984, 53:2002-2007. FA Buurmeijer, DC Hermans: The Family Dimension Scale as an aid to family diagnosis / De Gezins Dimensie Schalen als hulpmiddel bij gezindiagnostiek. Tijdschrift voor Psychotherapie 1985, Vol 11:336-346. DH Olson: Circumplex Model VII: validation studies and FACES III. Fam Process 1986, 25:337-51. E van der Ploeg, TT Mooren, RJ Kleber, PG van der Velden, D Brom: Construct validation of the Dutch version of the impact of event scale. Psychol Assess 2004, 16:16-26. M Horowitz, N Wilner, W Alvarez: Impact of Event Scale: a measure of subjective stress. Psychosom Med 1979, 41:209-18. HJ Eysenck, & Eysenck, S. B. G.: Manual of the Eysenck Personality Questionnaire. In: Book Manual of the Eysenck Personality Questionnaire. (Editor ed.^eds.). City: Hodder and Stoughton; 1975. HG Prigerson, PK Maciejewski, I Reynolds, Charles F., AJ Bierhals, JT Newsom, A Fasiczka, E Frank, J Doman, M Miller: Inventory of complicated grief: A scale to measure maladaptive symptoms of loss. Psychiatry Research 1995, 59:65-79. PA Boelen, J Van Den Bout, J De Keijser, H Hoijtink: Reliability and validity of the Dutch version of the inventory of traumatic grief (ITG). Death Stud 2003, 27:227-47. J Hox: Multilevel analysis: techniques and applications. Mahwah, NJ: Erlbaum; 2002. H Goldstein, J Rasbash, I Plewis, D Draper, W Browne, M Yang, G Woodhouse, M

Chapter 7 Healy: A user's guide to MLwiN. In: Book 40. EK Chan, I O'Neill, M McKenzie, A Love, A user's guide to MLwiN. (Editor ed.^eds.). DW Kissane: What works for therapists City: Multilevel Models Project, Institution conducting family meetings: treatment of Education, University of London; 1998. integrity in family-focused grief therapy 39. S Nolen-Hoeksema, J Larson: Coping with during palliative care and bereavement. J loss: Mahwah, NJ: Erlbaum; 1999. Pain Symptom Manage 2004, 27:502-12.

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Summary and general discussion

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The aim of the first part of the studies described in this thesis was to examine the relation of psychological and somatic symptoms in terminally ill cancer patients, with euthanasia. Since studying a vulnerable patient group has several methodological challenges this concluding chapter will start with a description of the study design, followed by a description of the cohort of terminally ill cancer patients that was formed to study the issues outlined above. Thereafter the main findings of the first part of this thesis (Chapter 2 to 5) will be summarised and discussed. The aim of the studies described in the second part of this thesis was to describe the consequences of euthanasia in terminally ill cancer patients on grief among the bereaved relatives and other predictors of complicated grief. After a short introduction, the main findings will be summarised and discussed. PART I – DEPRESSION IN TERMINALLY ILL CANCER PATIENTS AND EUTHANASIA

Introduction and study design The Netherlands is the first country to legally regulate euthanasia and to study the rate of euthanasia requests systematically. From these nation-wide studies among physicians, we know the rate of euthanasia is highest (i.e. 7.4%) among cancer deaths (1-3), and the estimated interval by which the patient's life is shortened is less than 1 month in most cases (4). These studies have also shown that two-thirds of the requests for euthanasia never develop into a serious and persistent request (1-3), but what leads some patients to discuss euthanasia, and what leads some of them to make an explicit request has not been studied. The concern that sub-optimal palliative care would urge patients to do an explicit request for euthanasia, and the view of a request for euthanasia as a symptom of underlying depression, has prompted several studies (5-22). However none of these studies assessed symptoms as reported by patients themselves, and none of the studies was performed in an environment where euthanasia is generally accepted and legally regulated. To assess whether depression or other psychological or somatic symptoms are related to discussing or requesting for euthanasia, we planned to perform a prospective case-control study within a cohort that consisted of patients with a relatively high risk of requesting euthanasia: terminally ill cancer patients. Because it was not feasible to include 102


patients through general practitioners, we decided to limit the study population to patients treated at an academic hospital, namely the University Medical Center Utrecht. This hospital is one of the ten tertiary referral centres for cancer patients in The Netherlands. Each year almost 170 cancer patients die in this hospital, approximately 7% of these are euthanasia cases. The following departments were willing to participate in the study: gynaecology, medical oncology, lung diseases, and head and neck surgery, together these departments contain about 80% of all cancer patients of the University Medical Center Utrecht. The treating physicians determined whether a patient was eligible for inclusion. Inclusion criteria were: an estimated life expectancy of less than 3 months, the patient was aware the cancer was untreatable and the patient was able to answer questions regarding mood state. The reasons the physicians gave for excluding a patient, were carefully noted. The reasons the patients gave for refusing to participate were also recorded. The researcher either visited the eligible (in-)patient in the hospital, or the (out-)patient was contacted by phone to explain the aim of the study. The aim of the study was described to the patients as ‘gaining insight into psychological symptoms of patients with incurable cancer and the relation with medical decisions at the end of life’. The term euthanasia was not explicitely mentioned since it is considered good clinical practise not to initiate talking about euthanasia.The patient is the one who has to bring up the topic. After informed consent was obtained the patient was asked to complete the study questionnaires (Hospital Anxiety and Depression Scale, Edmonton Symptoms Assessment Scale and Depression Adjective Checklist) by him/herself or with help from the researcher. Most inpatients chose the latter option and the questionnaire was then presented orally by the interviewer. A follow-up measurement was performed when a patient of the cohort explicitly and consistently requested euthanasia, and the euthanasia procedure was started. This procedure implies that the request is discussed in the medical team and if the team agrees, a second opinion from an independent physician is obtained. Among these patients and among a randomly selected sample of the rest of the cohort the presence of current and life-time depressive episodes was assessed by the Composite International Diagnostic Interview (CIDI-auto) (2325). More specifically at the moment a case was interviewed, two controls were randomly sampled from the cohort and contacted for an interview. The 103

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physicians were blind for the findings of both measurements because we did not want to influence standard care. According to the guidelines for handling euthanasia requests from The Royal Dutch Medical Association a request has to be voluntary, well considered and consistent, but a psychiatric consultation is not mandatory(26). Patients Between September 1999 and August 2003 385 cancer patients were traced who had a life expectancy of less than 3 months, 187 of these patients were deemed unable, and therefore also non-eligible, to participate in the study by their physician. We asked 198 patients to participate. Of these, 40 refused (4 because of fatigue, 6 were too ill, 8 too distressed, 2 did not accept being incurable, 2 were not aware of being incurable, 18 for other reasons such as not being interested) and 18 gave consent but were not able to complete the questionnaire. The cohort consisted of predominantly female patients (64%). The tumour site was mostly gynaecological (35.8%) or urological (16.8%) and most patients were hospitalised; 15% filled in the questionnaire at home and returned it by mail. Anti tumour treatment was discontinued at a median period of 2.7 months before inclusion. Two participants had more than 10% missing data on the Hospital Anxiety and Depression Scale and were therefore excluded from the analysis examining depression, leaving 138 patients in Chapter 2. Results of Chapter 3 were based on a subsample of 96 patients who were questioned about positive mood. Eleven patients were still alive at the moment the data were analysed for Chapter 4. For Chapter 5, fourteen patients were excluded because information was lacking about whether they had discussed euthanasia with their physician. Main findings At baseline thirty-two patients (23%) had a depressed mood as assessed by the HADS questionnaire (score > 20 points) (Chapter 2). A total of 75 (59%) patients considered and discussed euthanasia with their physician, some discussed it when the cancer was first diagnosed, but most discussed it when the cancer became incurable, or at the end of life (Chapter 5). Patients who discussed euthanasia were less often religious (Chapter 5). Thirty-two patients from the cohort made an explicit request for euthanasia and twenty patients died by 104


euthanasia, two in a hospice, eight at home and ten in our hospital. Chapter 4 showed that 14 of 32 patients (44%) with depressed mood at inclusion, requested euthanasia during follow-up. Among the 105 patients without depressed mood at inclusion were 16 (15%) who requested euthanasia during follow-up. The risk of a request for euthanasia for patients with a depressed mood was 4.1 (95% confidence interval (CI) 2.0 to 8.5) times higher than that of patients without depressed mood at inclusion. Of the 12 patients with an explicit request for euthanasia, 2 had a Major Depression at the time of the interview. None of the seventeen patients without a request for euthanasia had a Major Depression at the time of the interview (Chapter 4). Among the 75 patients who had at some point discussed euthanasia, level of pain, level of insomnia and presence of a depressed mood were positively associated with explicitly requesting euthanasia (Chapter 5). Pain was independently associated with more (odds ratio, 1.37 [95% CI, 1.06 to 1.77]), and being religious was independently associated with fewer (odds ratio, 0.21 [95% CI, 0.06 to 0.76]) explicit requests for euthanasia. Feeling dependent (ESAS), and functional status (Karnofsky) were not related to a request (Chapter 5). A single question into depression on a ten-point digit scale was able to discriminate the depressed (score > 20 points on the Hospital Anxiety and Depression Scale) from the non-depressed (Chapter 2). A score of >2 on the single depression question had a positive predictive value of 30/74 (40%); a score of < 2 had a negative predictive value of 61/63 (96%). Thus, a score of < 2 virtually excluded a depression as assessed by the HADS. Somatic symptoms, most particularly drowsiness, were associated with depression in this terminally ill population (Chapter 2). Most terminally ill cancer patients reported one or more positive mood states: a positive mood state such as ‘being interested’ (endorsed by 65%) was more common than ‘feeling sad’ (endorsed by 56%) (Chapter 3). As was expected, depressed patients indicated less positive mood than non-depressed patients. Discussion We were the first to examine the relation between psychological and somatic symptoms and incidence of euthanasia requests among terminally ill cancer patients. Moreover, previous studies never systematically investigated symptoms related to an explicit request for euthanasia among patients who previously considered and discussed it. The representativeness of the sample 105

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will be discussed first, because this has important implications for the generalisability of the findings. Thereafter we will discuss the way we assessed depression, followed by the main conclusions and clinical implications. Representativeness Patients were recruited inthe University Medical Center Utrecht. This hospital is one of the ten tertiary referral centres for cancer patients in The Netherlands, and patients may have been referred to this hospital for complex problems requiring specialised treatment. Therefore the sample may not be representative for the general population of terminally ill cancer patients. For practical and ethical reasons we had to restrict inclusion to patients who were aware of their limited life expectancy and were able to answer questions regarding physical and mental well-being. Therefore, the group represents a relatively ‘fit’ selection of all patients dying from cancer. The prevalence of depression in our sample was comparable to other studies (27, 28), but since other studies have had to deal with the same difficulties, this does not rule out the possibility that psychological and physical symptoms are commonly underestimated. Yet, there is no reason to expect that this could affect the relation of psychological and physical symptoms with requests for euthanasia. The percentages of people discussing (59%) and requesting (22%) euthanasia in our study, agree with what would be expected based on the nation wide studies: 7% of all cancer deaths are by euthanasia, and since two thirds of all patients discussing euthanasia do not come to make an explicit request and only one third of all explicit requests is carried out, this would imply that 21% of all cancer patients explicitly request euthanasia and 63% discuss euthanasia. The mean age, marital status, number of children and prevalence of religion in our study was similar to that of previous cohorts of cancer patients that died in our hospital (29). Moreover, no differences were found between the patients that participated and those who refused to participate concerning age and gender. Therefore we conclude that the cohort studied was representative of a relatively ‘fit’ population of cancer patients seen by the co-operating departments of the University Medical Center Utrecht. Assessment of depression In the introduction we pointed out that diagnosing depression according to the DSM-IV classification can be difficult in terminally ill cancer patients, 106


particularly because according to this classification symptoms may not be due to medication or a medical condition. The Hospital Anxiety and Depression Scale (HADS), that was used in this study, is generally used as a screening tool for depressive disorders in oncology and palliative patients as it specifically excludes references to somatic items. Another advantage of the HADS is that it does not ask for suicidal thoughts, and thus avoids contamination with a wish for euthanasia, which was important regarding the aim of our study. Furthermore, although it is not a diagnostic tool, it does predict the development of Major Depression in terminally ill cancer patients(30). To diagnose “depressed mood” we used a cut-off score of 20 for the total scale of the HADS, as recommended when using it for screening for depression in cancer patients in palliative care(31). The use of the total scale was also recommended in a Dutch validation study of this questionnaire (32). All in all, it seems reasonable to accept that patients with a score higher than 20 on the HADS may be described as patients with a depressed mood. The Composite International Diagnostic Interview is a structured clinical interview that is used to diagnose Major Depression, based on the criteria of the ICD-10 and DSM-IV classification system. It has good to excellent psychometric properties (23-25). Unfortunately we did not succeed in interviewing sufficient patients for valid inferences. Nevertheless the findings from this subgroup do not contradict the findings based on the HADS interview, which was performed in all patients. Clinical implications and future research Depressed mood had the strongest relation with an explicit request for euthanasia in the whole group, and at the same time it became clear that not all patients who request euthanasia had a depressed mood at inclusion (i.e. of 32 patients with a request 14 had a depressed mood at inclusion), or a Major Depression (two out of twelve) at the time of the request. The assumption that a request for euthanasia is a symptom of underlying Major Depression can thus be disputed. We therefore agree with the conclusion of a previous study that standard psychiatrist consultation should not be mandatory, since the benefits should be balanced against the disadvantages(26). We would encourage physicians to consult a psychiatrist whenever they have doubts about whether the depressed mood of a patient affects his or her decision making ability.

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The question whether treatment of depression in terminally ill cancer patients would lower the prevalence of requests for euthanasia needs further investigation. Apart from this, we feel it is important to offer treatment of depression to patients, since depression not only has a negative impact on other symptoms and the quality of life of patients, but also on their family (33, 34). Moreover, despite the fact that depression is common in this group, the knowledge that positive mood is even more prevalent (80% reported to have at least one positive mood state) may help to see that depression is not ‘normal’. Therefore we would urge oncologists and general practitioners to systematically ask patients with advanced cancer to rate depressed mood on a ten-point digit scale, and refer patients who score higher than 2 for more thorough screening by a psychologist or a psychiatrist. In this way early detection of depression will improve so that appropriate treatment (counselling or medication) might be initiated. Though pain did not have a strong association with the risk for a euthanasia request in the whole group, it was independently associated with an explicit request for euthanasia in the group of patients that already discussed euthanasia with their physician. This suggests that among the patients who consider and discuss euthanasia, the intensity of pain does add to the decision of making an explicit request. The findings are in line with a previous study where pain was found to be reported more frequently in the files of patients who died by euthanasia, than in those who did not die by euthanasia (29). Also in our study, pain was more often documented as ‘not adequately treated’, despite strong efforts to treat it, in the files of patients who did an explicit request for euthanasia, then in the files of those who did not (unreported findings from this study). In 10% of all terminally ill cancer patients it is not possible to treat pain symptoms adequately (35-37), therefore this finding does not mean that the care for these patients was sub-optimal, but it does say something about the importance of improving pain control. In advanced cancer patients, pain is treated by utilizing the analgesic ladder proposed by the World Health Organization, which ends with opioids (38). However, opioids have the side effect of making people drowsy, and some people wish to take leave in full conscience. Terminal sedation is no option for them. The development or better availability of ways of pain relief that do not make people drowsy, might be of help to them.

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It would be interesting to study whether improving pain control would indeed prevent these patients from doing an explicit request. From the data that were presented it seems logical to conclude that pain added to the decision making of the request, however we cannot rule out the possibility of another variable influencing both pain and the decision making of the request. It would also be interesting to know, whether these findings can be generalized to other terminally ill populations. PART II – GRIEF IN THE RELATIVES OF TERMINALLY ILL CANCER PATIENTS Introduction and study design Complicated grief, a condition associated with enduring mental and physical health morbidity (39), is the most prevalent psychopathological response to a bereavement event. Unnatural death, such as suicide, can cause severe grief reactions in family members (40, 41). As euthanasia is also considered as an unnatural death, it has been suggested that euthanasia may induce complicated grief (42). However, the grief experienced by family members in suicide cases differs from grief after euthanasia, mainly because the relatives of the latter have had the opportunity to say goodbye, which is seldom the case in suicides. To assess how euthanasia in terminally ill cancer patients affects the bereaved a cohort study was conducted among 189 bereaved family members and close friends of cancer patients who died by euthanasia and 316 bereaved family members and close friends of comparable cancer patients who died a natural death between 1992 and 1999 (Chapter 6). The results of this retrospective cohort study gave rise to new questions about the role of awareness of impending death in the development of complicated grief, therefore a prospective study was conducted that aimed to find predictors of complicated grief. Since professional support during the terminal illness has been found to protect against complicated grief and was found to be more efficient than intervening after the patients death (43), it was important to assess predictors during the terminal illness period . This prospective study was linked to the cohort study among the patients in part I of this thesis.

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We asked patients permission to contact their relatives. The final population comprised 127 relatives of 55 patients, reflecting 64% of the relatives originally approached and an 81% participation rate. Main findings The bereaved of cancer patients who died by euthanasia had less traumatic grief symptoms: adjusted difference was -5.29 (95% confidence interval -8.44 to -2.15); less present feeling of grief: 2.93 (0.85 to 5.01); and less posttraumatic stress reactions -2.79 (-5.33 to -0.25) than the bereaved of comparable cancer patients who died of natural causes (Chapter 6). This was independent of other risk factors. Being the partner of the patient (and not a sibling, adult child or second degree relative), female gender, neuroticism and avoidance were independent predictors of complicated grief among relatives of terminally ill cancer patients (Chapter 7). High family cohesion predicted complicated grief in this prospective study, though this was not independent from the relation between partners and complicated grief, and partnership was a better predictor than family cohesion (Chapter 7). If patients discussed euthanasia, it was more likely that relatives talked with the patient about impending death, however this did not predict less complicated grief (Chapter 7). Discussion To appreciate the findings, several limitations regarding the designs of these studies need to be discussed. First, non-response may have influenced the findings. In the retrospective study the responses from the relatives of euthanasia death were somewhat higher than that of the relatives of natural death, 75% versus 69% respectively. Persons with greater feelings of grief are more prone to non-response than persons with less feelings of grief.19 Therefore, it seems more likely that the found differences in Chapter 6 are an underestimation rather than an overestimation due to non-response. In the prospective study the participation rate (81%) was very good, however it is possible that the cancer patients selected relatives for the study who were doing relatively well. Also the contact persons of the deceased patients in Chapter 6 could have selected subjects for the study who were doing well. It is unlikely that this would be different for relatives from the patients who died from natural causes and thus cannot explain our findings from Chapter 6. The 110


predictors found in Chapter 7 would probably be even stronger if more relatives with severe grief would have participated, and perhaps even more predictors would have been found, but it is unlikely that different predictors would have been found. Secondly, it is important to realise that in the Netherlands many patients die at home (40%), especially oncology patients (48% of all cancer deaths) (44). Therefore, the study population in Chapter 6 may not be representative for family members of all deceased oncology patients. It might be possible that these relatives experienced the dying process in the hospital in a different way than the relatives of cancer patients who died at home. We therefore have to restrict the interpretation of the findings in Chapter 6 to patients dying in hospital. The places where the patients from the relatives in Chapter 7 died, agreed with that of the general population (55% died at home, 22% in the hospital and 16% in a hospice). We found no relation between the place of death and complicated grief in this study (unreported results). The full open awareness context, wherein patients and relatives are able to discuss euthanasia and say farewell, was hypothesised to play an important role in the bereavement process afterwards in Chapter 6. In the prospective study half of the patients discussed euthanasia, 12 patients did an explicit request for euthanasia, and 7 died by euthanasia. Because of the low number, the effect of dying by euthanasia on grief in the relatives could not be tested in this study. Patients who discussed euthanasia with their physician were more likely to have relatives that talked with them about impending death. However, a beneficial effect on grief could not be demonstrated in Chapter 7. Because there were no relatives who never thought of the impending death of the patient and only ten relatives never talked about the impending death with anyone, only full open awareness (i.e. thinking and talking with the patient about the impending death) could be compared to limited awareness (thinking but not talking about the impending death with the patient) and not to closed awareness (i.e. not thinking or talking about impending death). Chapter 7 did show that avoiding feelings and thoughts concerning the information that the disease of the patient one could not be cured, had an adverse relation with grief after the loss.

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Clinical implications and future research We concluded Chapter 6 with the statement that the results should not be interpreted as a plea for euthanasia, but as a plea for the same level of care and openness in all patients who are terminally ill. What was not clear from this study is whether relatives of patients who died by euthanasia were better off all the time, or if they were further on in their process of grief. It would be interesting to study the course of grief in relatives who die by euthanasia in comparison with the course of grief in relatives of patients who die naturally. This would require a large sample of relatives of patients who potentially will ask for euthanasia. To circumvent the problem we encountered that patients might be selecting relatively healthy relatives, we would advise to directly approach the relatives. Although we think relatives are able to decide for themselves if they want to participate, the Medical Ethical Committee of our hospital would not allow us to approach relatives without first asking permission of the patient. In light of the results of Chapter 7 we suggest that partners who engage in avoidance strategies after hearing the cancer of their loved one is incurable, would seem most likely to benefit from interventions targeted at those strategies. Since we could not compare partners to parents, or children younger than 15 years, our results show that partners are more affected than siblings, adult children and second degree relatives. From previous studies we know that parents are also at a high risk (45) and studies show that widowers are at a higher risk than widows (46). Although the disease of the patient often affects a whole family, and family-centred care is a desired goal in palliative care (47), we doubt whether family focused interventions are always warranted, since siblings, adult children and second degree relatives do not generally have a high risk of developing complicated grief. Moreover, only those at high risk are likely to benefit from support and supporting relatives who are not at high risk may even be harmful (48). One argument in favour of a clinical approach that screens for families rather than individuals at high risk was that greater levels of psychosocial morbidity were present in families whose functioning as a group was poorer (49). However this does not say anything about the efficiency of a family focused approach in comparison with a intervention targeted only at partners. A study comparing the costs and benefits of both approaches needs to been done to test which approach should be implemented.

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Curriculum Vitae Marije van der Lee was born on March 22, 1973, in Amsterdam, The Netherlands. After completing secondary education (VWO) at the St. Vituscollege in Bussum in 1991, she studied industrial design engineering in at the Technical University in Delft. In 1993 she started studying psychology at the University of Amsterdam. In 1998, she started working as a researcher at The Helen Dowling Institute. In 2000 she started working on her Ph.D. on the project that has resulted in the present dissertation. The research was conducted at the Department of Clinical Psychology, in close collaboration with the University Medical Center Utrecht. From 2003? to 2005, she has also held a part-time position as lecturer at the Department of Clincial Psychology. Since February 2003, she has been working as a lecturer at the Institute for general practitioners at the Erasmus University Rotterdam.

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